A 3-month-old fawn from a group of 12 captive white-tailed deer (Odocoileus virginianus) displaying cutaneous lesions was presented to the Mississippi Veterinary Research & Diagnostic Laboratory for necropsy. Postmortem examination identified multiple discrete, round, alopecic, flat, proliferative dermal lesions scattered along the skin of the lips, muzzle, pinna, ventral thorax, medial limbs, and most notably the abdomen. Multiple ulcers were present on the commissures of the lips, dorsal surface of the tongue, and left caudal buccal surface of the oral cavity. The abdomen was filled with fibrinopurulent exudate and ruminal contents. Multiple to coalescing transmural ulcers were identified in the rumen. Histopathological evaluation of the skin revealed markedly thickened epidermis and focal areas of superficial dermal fibrosis, intracytoplasmic, eosinophilic inclusions in swollen keratinocytes and lymphocytic and plasmacytic perivascular dermatitis. The rumen ulcers were surrounded with necrotic cellular debris mixed with fibrin, bacteria, hemorrhages, and a collection of mixed inflammatory cells. Some swollen ruminal mucosal epithelia had eosinophilic intracytoplasmic inclusions. Poxvirus was isolated from the skin and rumen tissue specimens. Electron microscopy detected viral particles with poxvirus morphology. Polymerase chain reaction assays detected A21, a gene conserved within family Poxviridae, in the skin and rumen tissues. Phylogenic analysis of the A21 sequences indicated that the viral isolate (M10-9055) was closely related to known members of genus Cervidpoxvirus. In conclusion, findings indicate that Deerpox virus can produce extensive lesions in white-tailed deer.