A 10.5-yr-old male spotted hyena (Crocuta crocuta) developed acute, severe erythematous and ulcerative dermatitis of the hindquarters, feet, face, and ears 19 days after receiving a recombinant canary pox vectored canine distemper vaccine. Biopsies of the lesions supported a diagnosis of erythema multiforme (EM), which is an immune-mediated disorder that can occur days to months after exposure to antigenic stimuli. During the lengthy recovery, esophageal regurgitation and ulceration developed either as complications of the disease or secondary to therapy. The esophageal disease was managed with metoclopramide, sulcrafate, omeprazole, and frequent feedings. The distemper vaccine is postulated to have been the inciting cause of EM in this animal.