Orthopoxviruses (OPXVs) are of continuing concern due to their zoonotic potential and potential use in bioterrorism. Increases in OPXV infections have recently been seen in animals and humans. This article describes a rapidly progressive infection in an Italian cat. OPXV infection was confirmed by PCR testing, and the virus isolated and identified. Although cats more often become infected with OPXV through infected wild rodents carrying variants of cowpoxvirus, this virus was only distantly related to the more typical cowpoxvirus. It was more closely related to ectromelia virus (ie, mousepox) and likely represents a novel OPXV. The true reservoir must be investigated, given its zoonotic potential, and clinicians should be cautious when handling cats with skin disease.