Smallpox is believed not to occur naturally in species other than man. However, reports of several epizootics of an exanthematous disease, similar to smallpox, in wild monkeys have raised the question of a simian reservoir. If such a reservoir for smallpox exists, the eradication of this disease from the world would be a difficult or impossible task. Transmission of smallpox in Macaca irus has been studied to determine whether transmission occurs and if infection chains can be maintained by this species.Transmission was consistently accomplished by both contact and aerosol routes. In the contact transmission studies, the smallpox infection was maintained through 6 passages but was lost with the seventh passage. The virulence of the virus did not appear to increase as the virus was serially passed in monkeys. Continuing studies of the possible occurrence of smallpox and of monkeypox in simian populations are warranted.