Human monkeypox was first identified in 1970 in the Democratic Republic of the Congo. Extensive studies of this zoonotic infection in the 1970s and 1980s indicated a largely sporadic disease with a minority of cases resulting from person-to-person transmission, rarely beyond two generations. In August 1996, an unusually large outbreak of human monkeypox was reported, and cases continued through 1997 with peak incidence in August 1996, March 1997 and August 1997. Preliminary results from the field investigations in 1997 suggest a new epidemiological pattern where a majority of secondary cases result from person-to-person transmission, and a clinically milder disease. But there is preliminary laboratory evidence of a simultaneous outbreak of varicella in the same geographic region which will undoubtedly modify these preliminary results. Since smallpox was eradicated and vaccinia vaccination terminated in this region, the population of susceptible individuals has grown. The use of vaccination to protect the population at risk, however, must take into account HIV prevalence and the risk of generalized vaccinia when using vaccinia vaccine in populations where HIV is known to be present.