Within the clinical spectrum of erythema multiforme, two subgroups have been recently identified: recurrent erythema multiforme and the rare persistent erythema multiforme. Two additional cases of persistent erythema multiforme are described. Lesions were widespread and resistant to traditional therapies. One of the patients had an underlying malignancy; the other exhibited a symptom complex characterized by fatigue, fever, sore throat and lymphadenopathy, and an abnormal Epstein-Barr virus serologic profile suggestive of endogenous reactivation of Epstein-Barr virus infection.