Abstract. An outbreak of severe cutaneous disease associated with an orthopoxvirus in horses in southern Brazil is described. Fourteen Crioulo mares and foals from a husbandry farm developed papules, and vesicles progressing to proliferative and exudative lesions on the muzzle, external nares, and external and internal lips. The vesicles eroded, and the proliferative lesions eventually bled and progressed to moist crusts and scars. The clinical signs lasted approximately 6-12 days, after which the animals progressively recovered. Direct electron microscopy of skin biopsies revealed brick-shaped, 250-300-nm virus particles with orthopoxvirus morphology. Histological examination of the lesions revealed vacuolar degeneration of the cells of the stratum spinosum and the presence of large intracytoplasmic, eosinophilic inclusion bodies. Polymerase chain reaction amplification of poxvirus A-type inclusion body gene confirmed the presence of orthopoxvirus DNA in horse tissues. Inoculation of tissue homogenates into the chorioallantoic membrane of chicken embryonated eggs and intraperitoneally in mice resulted in pock-like lesions with the microscopic appearance of poxvirusinduced histopathology. Taken together, these results demonstrate the association of an orthopoxvirus with the outbreak of cutaneous disease in horses. The origin of the agent causing the outbreak is uncertain because no similar condition has been reported in Brazil.