Parapoxviruses are a genus of the double-stranded DNA family of poxviruses that infect ruminants, and zoonotic transmission to humans often results from occupational exposures. Parapoxvirus infection in humans begins with an incubation period of 3 to 7 days, followed by the development of one or more erythematous maculopapular lesions that evolve over the course of several weeks into nodules. In 2009, parapoxvirus infection was diagnosed in two deer hunters in the eastern United States after the hunters had field-dressed white-tailed deer. We describe the clinical and pathological features of these infections and the phylogenetic relationship of a unique strain of parapoxvirus to other parapoxviruses. Deer populations continue to increase, leading to the possibility that there will be more deer-associated parapoxvirus infections.