The 13 deadliest outbreaks on record, ranked by the midpoint of the published estimate range for deaths. Counts for ancient and medieval events are scholarly estimates with very wide ranges, so treat every rank as approximate.
Pictured: the TED-Ed lesson “How we conquered the deadly smallpox virus,” on smallpox, #1 with an estimated 300–500 million deaths in the 20th century.
Rank
Event
Deaths, midpoint (millions)
Low (millions)
High (millions)
Years
Disease / pathogen
Type
Era
1
Smallpox (20th century only)
400
300
500
1900–1979
Smallpox (variola virus)
Viral
Modern
2
Black Death
137.5
75
200
1346–1353
Plague (Yersinia pestis)
Bacterial
Medieval
3
Spanish flu
58.5
17
100
1918–1920
Influenza A (H1N1)
Viral
Modern
4
Plague of Justinian
57.5
15
100
541–549
Plague (Yersinia pestis)
Bacterial
Medieval
5
HIV/AIDS pandemic
47.45
33.8
61.1
1981–present
HIV
Viral
Modern
6
Third plague pandemic
13.5
12
15
1855–1960
Plague (Yersinia pestis)
Bacterial
Modern
7
COVID-19 pandemic
11.0
7.1
14.9
2019–present
SARS-CoV-2
Viral
Modern
8
Cocoliztli epidemic (Mexico)
10.0
5
15
1545–1548
Unconfirmed (Salmonella or a viral hemorrhagic fever)
Disputed
Early modern
9
Antonine Plague
7.5
5
10
165–180
Probably smallpox
Viral
Ancient
10
Mexico smallpox epidemic
6.5
5
8
1519–1520
Smallpox (variola virus)
Viral
Early modern
11
Asian flu
2.5
1
4
1957–1958
Influenza A (H2N2)
Viral
Modern
11
Hong Kong flu
2.5
1
4
1968–1969
Influenza A (H3N2)
Viral
Modern
13
Russian flu
1.0
1
1
1889–1890
Influenza or human coronavirus OC43 (disputed)
Viral
Modern
No matching rows.
How this is ranked. Each event is ordered by the midpoint of its estimate range, (Low + High) ÷ 2, in millions of deaths; the two flu events tied at 2.5 share rank 11. Ranges follow the figures in Wikipedia’s “List of epidemics and pandemics” and the event articles it links to, which in turn summarize scholarly work.[1] Smallpox (WHO), HIV/AIDS (UNAIDS) and COVID-19 (WHO) use those bodies’ own published figures instead, because they are measured or modelled counts rather than historical reconstructions. Early-history figures, especially the Black Death, the Plague of Justinian, the Antonine Plague and the Cocoliztli epidemic, are estimates with wide ranges, and some scholars argue they are too high. Smallpox scope: the figure covers only the 20th century (1900–1979), not the disease’s whole history, and is an ongoing-disease total rather than a single outbreak, so it is the loosest fit on the list.[2]COVID-19 counts: the low figure is WHO-reported deaths (about 7.1 million as of mid-2026; the total on October 6, 2026 may differ slightly), and the high figure is WHO’s estimate of excess deaths for 2020–2021 alone (14.9 million, range 13.3–16.6 million), so the true full-pandemic toll may be higher.[8] HIV/AIDS shows UNAIDS’ cumulative deaths since the epidemic began (44.2 million best estimate, 33.8–61.1 million range), still growing slowly each year.[6] The Spanish flu range spans a 2018 study’s 17 million to the often-cited 100 million.[4] Plague still occurs in small numbers today but is treatable with antibiotics.[3]
The Top 10
#1
Smallpox, 20th century — 300–500 million
WHO estimates that smallpox caused 300–500 million deaths in the 20th century alone, before it was declared eradicated in 1980.[2] It was a mass killer for thousands of years, but the scope here is deliberately limited to the final eighty years, when mortality can be estimated best. Even in 1967, WHO estimated 15 million cases and two million deaths in a single year.[2] It remains the only human disease ever eradicated, thanks to vaccination campaigns.
#2
Black Death — 75–200 million
The plague that peaked in Europe from 1346 to 1353 is estimated to have killed 75–200 million people across Eurasia, and between 30% and 60% of Europe’s population.[3] It was caused by the bacterium Yersinia pestis, and the world’s population is thought not to have recovered to its pre-plague level until the 17th century.[3] It is the largest single event in this ranking by deaths.
#3
Spanish flu — 17–100 million
The 1918–1920 H1N1 influenza pandemic infected roughly a third of the world’s population. Mortality estimates vary more than for almost any modern event: CDC cites at least 50 million deaths, a 2018 study put the toll near 15–17 million, and some estimates reach 100 million.[4] The name is misleading: Spain’s uncensored wartime press simply reported it early.
#4
Plague of Justinian — 15–100 million
The first recorded plague pandemic began in 541 in the Byzantine Empire and returned in waves for two centuries. Traditional estimates run from about 15–25 million to as many as 100 million deaths, but historians disagree sharply: a 2019 study by Mordechai and colleagues argued the surviving evidence does not support such catastrophic numbers.[5] Its position here is therefore one of the least certain.
#5
HIV/AIDS pandemic — 33.8–61.1 million
UNAIDS estimates that about 44.2 million people have died of AIDS-related illnesses since the epidemic began in the early 1980s, with an uncertainty range of 33.8–61.1 million.[6] The annual toll has fallen sharply, by 73% from its 2004 peak, thanks to antiretroviral treatment, with about 570,000 deaths estimated in 2025.[6] It is the only event in the top five that is still adding to its total.
#6
Third plague pandemic — 12–15 million
Beginning in Yunnan, China, in 1855 and considered active until 1960, this plague pandemic spread to every inhabited continent. Most of its deaths, an estimated 10–12 million, occurred in British India, with about 2.2 million in China.[7] It was the first plague pandemic studied with modern science, and the one in which the bacterium and its transmission by rat fleas were identified.
#7
COVID-19 pandemic — 7.1–14.9 million
WHO’s count of reported COVID-19 deaths stands at roughly 7.1 million as of mid-2026, but reported figures miss many deaths. WHO’s excess-mortality study estimated 14.9 million deaths associated with the pandemic in 2020 and 2021 alone, including indirect deaths from disrupted health care.[8] Other researchers’ full-pandemic estimates are higher still. The video shown covers WHO’s response rather than the death toll.
#8
Cocoliztli epidemic (Mexico) — 5–15 million
“Cocoliztli” is the Nahuatl word for pestilence, and the 1545 outbreak is counted among the worst events in the demographic collapse of 16th-century Mesoamerica. Estimates run from 5 to 15 million deaths, though one recent popular account cites far fewer, and the cause remains debated: ancient DNA from victims showed Salmonella Paratyphi C, while researchers such as Rodolfo Acuña-Soto have argued for a viral hemorrhagic fever.[9] This is the least certain figure on the list.
#9
Antonine Plague — 5–10 million
Named for the Roman emperor Marcus Aurelius Antoninus, this outbreak struck the Roman Empire from 165 to 180 CE. Modern estimates put deaths at 5–10 million, perhaps a tenth of the empire’s population, and Galen’s description of pustules has led most researchers to conclude it was smallpox.[10] Sources describing the cause are second-hand, so the identification is probable rather than certain.
#10
Mexico smallpox epidemic — 5–8 million
Smallpox reached the Americas with Spanish expeditions in 1519, and the first wave in 1520 is estimated to have killed 5–8 million people across Mesoamerica, between a third and a half of the population in some accounts.[11] It struck while the Aztec capital was already under attack, and is widely regarded as one of the most consequential epidemics in the history of the Americas.
Wikipedia, “List of epidemics and pandemics” — https://en.wikipedia.org/wiki/List_of_epidemics_and_pandemics (primary reference for most ranges: Black Death 75–200 million, Spanish flu 17–100 million, Plague of Justinian 15–100 million, third plague pandemic 12–15 million, Cocoliztli 5–15 million, Antonine Plague 5–10 million, Asian and Hong Kong flu 1–4 million each, Russian flu about 1 million), cross-checked against the individual articles below.
World Health Organization estimate of 300–500 million smallpox deaths in the 20th century, as cited in Wikipedia, “History of smallpox” — https://en.wikipedia.org/wiki/History_of_smallpox; SAGE Encyclopedia of Disaster Relief, “Smallpox, 20th century”; TED-Ed, “How we conquered the deadly smallpox virus” (Simona Zompi).
Wikipedia, “Black Death” — https://en.wikipedia.org/wiki/Black_Death; The Collector, “How Many People Died From the Black Plague?”; TED-Ed, “The past, present, and future of the bubonic plague” (Sharon N. DeWitte).
Wikipedia, “Spanish flu” and list above; CDC, “1918 Pandemic (H1N1 virus)” (at least 50 million deaths); NIVEL, “Reassessing the global mortality burden of the 1918 influenza pandemic” (2018); University of Cambridge, “Spanish Flu: A Warning from History”; US Department of Health and Human Services, “We Heard the Bells: The Influenza of 1918” (YouTube).
Wikipedia, “Plague of Justinian” — https://en.wikipedia.org/wiki/Plague_of_Justinian; Mordechai et al., “The Justinianic Plague: An inconsequential pandemic?”, PNAS (2019); Ohio State University Origins, “The Justinianic Plague”; “The Plague of Justinian – Past Pandemics” (YouTube).
UNAIDS, “Global HIV & AIDS statistics — Fact sheet” — https://www.unaids.org/en/resources/fact-sheet (44.2 million [33.8–61.1 million] AIDS-related deaths since the start of the epidemic; 570,000 in 2025; edition used was the latest returned by search, check the fact sheet for updates).
World Health Organization, “14.9 million excess deaths were associated with the COVID-19 pandemic in 2020 and 2021” (May 5, 2022) — who.int; WHO COVID-19 Dashboard and Our World in Data, cumulative confirmed COVID-19 deaths (about 7.1 million as of June 2026); WHO, “How has WHO responded to COVID-19” (YouTube).
Wikipedia, “Cocoliztli epidemics” — https://en.wikipedia.org/wiki/Cocoliztli_epidemics; Acuña-Soto et al., “Megadrought and Megadeath in 16th Century Mexico,” Emerging Infectious Diseases (2002); Cosmos Magazine, “In conquered Mexico, almost a million died of salmonella in just five years.”
World History Encyclopedia, “Antonine Plague” — https://www.worldhistory.org/Antonine_Plague/; Brewminate, “The Antonine Plague in Second Century Rome”; “The Antonine Plague – Past Pandemics” (YouTube).
Wikipedia, “Hong Kong flu” (1–4 million; CDC cites about 1 million); Wikipedia, “1889–1890 pandemic” (about 1 million); Brussels Times, “Coronavirus possibly caused a million deaths in 1890, says Marc Van Ranst.”
