Human monkeypox is a severe smallpox-like illness caused by monkeypox virus (MPV); monkeypox occurs in sporadic outbreaks, and infection is enzootic among squirrels and monkeys in the rainforests of western and central Africa. In 1996, cases of monkeypox were reported from villages in the Katako-Kombe Health Zone, Kasai Oriental, Zaire (i.e., Democratic Republic of Congo). The World Health Organization (WHO), in collaboration with CDC, investigated this outbreak and identified 92 suspected cases with onset during February 1996-February 1997, and isolated MPV from lesions of active cases. Cases continued to be reported, and a new investigation was initiated by WHO and CDC in October 1997. This report summarizes the results of the field investigation, which indicate that this is the largest human monkeypox outbreak ever recorded.