In a prospective study of erythema multiforme, forty-two cases were selected with the use of defined criteria. In thirty-three cases (79%), the erythema multiforme occurred following a lesion of recurrent herpes simplex; in four cases (10%), it was related to administration of a sulfonamide drug. Herpes-associated erythema multiforme (HEM) was largely recurrent erythema multiforme minor and was characterized histopathologically by inflammatory changes, such as spongiosis and exocytosis, and by focal liquefaction degeneration of the basal cell zone of the epidermis. Sulfa-associated erythema multiforme (SEM) was a nonrecurrent illness with widespread cutaneous and mucosal damage associated with prominent histologic necrosis of epidermal cells. The deposition of C3 and fibrin along the dermoepidermal junction and the deposition of IgM, C3, and fibrin around dermal blood vessels by immunofluorescence microscopy were similar in both groups. Although HEM and SEM may have somewhat different clinical and histologic features, there is significant overlap in the pattern of tissue damage.