This survey of the clinical and epidemiological features of human cowpox, a rare but relatively severe zoonotic infection, is based on 54 cases, many unpublished, which we have studied since 1969. Patients present with painful, haemorrhagic pustules or black eschars, usually on the hand or face, accompanied by oedema, erythema, lymphadenopathy, and systemic involvement. Severe, occasionally fatal, cases occur in eczematous and immunosuppressed individuals, although cowpox has not yet been reported in anyone infected with the human immunodeficiency virus. Variations in the clinical features are described, and the differential clinical diagnosis of cowpox, parapox, herpes virus, and anthrax infections is discussed. The role of the laboratory in diagnosis is described, and the value of electron microscopy in providing rapid confirmation is emphasized. Care in taking a detailed history will assist in the initial clinical diagnosis, and a history of contact with domestic cats, particularly during July-October, is important. The possible influence of smallpox vaccination on the incidence and severity is discussed and discounted.