Cowpox is rare and used to occur only in Europe and Russia. The infection occurs in small mammals, cats and mice, and can sometimes appear in large animals, such as cattle and elephants. Humans can also be infected. The majority of cases exhibit vesiculopustular lesions on hands or face. The lesions ulcerate and subsequently develop a black crust. Differentiation from anthrax, mycosis, rickettsial chancre and tularaemia is necessary. Cowpox is caused by an orthopox virus and is related to variola and vaccinia virus. It is thought that infection occurs by direct contact with an infected animal such as a cat or a milking cow with lesions on her udder. The infection almost always remains localised at the site of inoculation. Rarely, there is dissemination via the lymphatics. Disseminated cowpox is extremely rare, but does exist. Spontaneous recovery is the rule with only a small residual scar as a consequence. Of three patients who have had severe infection, there were two with atopic eczema and a third had high fever for which he received steroids.

Cowpox has been confirmed in elephants, rhinos, anteaters and okapis and large Felidae. In large cats, cowpox manifests with pulmonary involvement leading to death. The reservoir host appears to be rodents, and cows are now considered to be incidental hosts.

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Cowpox virus possesses one of the largest genomes in the Orthopox virus genus. There are various cowpox strains including; Cowpox Brighton Red, Cowpox Daisy, Cowpox Austria, Cowpox Whipsinade, Cowpox Elephant, and Cowpox Carnivore. Cowpox can be differentiated from other orthopox viruses by the presence of both bright red hemorrhagic pocks on the chorioallantoic membrane and the presence of large A type inclusion bodies in infected cells. More recent techniques for differentiating pox viruses include PCR.