During the course of the recently concluded smallpox eradication program, a new human orthopoxvirus infection was discovered which is caused by monkeypox virus. The disease occurs sporadically in remote villages within tropical rain forests of West and Central Africa. The disease is rare; only 155 cases having been reported from 1970 to 1983. The symptoms and signs of human monkeypox resemble those of smallpox, differing significantly only in the occurrence of lymphadenopathy with human monkeypox disease. Of 155 cases, some 80% are believed to have resulted from infection from an as yet unknown animal reservoir; the rest occurred among unvaccinated close contacts among whom a secondary attack rate of 15% was observed. Although person-to-person spread appears to have occurred in some instances, few cases were observed in the third or fourth generation of transmission and none thereafter. Since 1982, the incidence of human monkeypox infections in Zaire has increased concomitant with an intensified surveillance program. Additional reasons which might explain the increased incidence are discussed. Further surveillance and research of this primarily zoonotic infection are warranted and are in progress.