We present the clinical features and course of 282 patients with human monkeypox in Zaire during 1980–1985. The ages of the patients ranged from one month to 69 years; 90% were <15 years of age. The clinical picture was similar to that of the ordinary and modified forms of smallpox. Lymphadenopathy, occurring in the early stage of the illness, was the most important sign differentiating human monkeypox from smallpox and chickenpox. The symptoms, signs, and the course of the disease in patients who had been vaccinated against smallpox differed significantly from those in unvaccinated subjects. Pleomorphism and “cropping” similar to that in chickenpox occurred in 31% of vaccinated and 18% of unvaccinated patients. The prognosis depended largely on the presence of severe complications. No deaths occurred among vaccinated patients. In unvaccinated patients the crude case-fatality rate was 11 070 but was higher among the youngest children (15%).