During 1992-96, outbreaks of buffalopox zoonosis were reported from different villages in Jalgaon, Dhule and Beed districts of Maharashtra State. In humans, pox lesions were observed on the hands whereas in affected buffaloes and cows the lesions were noticed mainly on the teats and udder. Twenty two virus strains were isolated from the skin scabs collected from infected humans and milch animals. Neutralizing antibodies were detected not only in the sera of affected humans but also in their contacts. Detection of antibodies in young individuals from endemic area, who were neither vaccinated for smallpox nor had any contact with buffaloes or history of any poxvirus disease, is suggestive of occurrence of subclinical infection. A few children who had no contact with infected animals also showed clinical manifestations with disseminated lesions on the face, arm and buttocks, and thus suspected to have acquired infection through their infected parents or other family members indicating a possible man to man transmission. Therefore, in the light of discontinuation of smallpox vaccination, buffalopox outbreaks need to be monitored carefully as this may emerge as a serious zoonotic disease in India.