Erythema multiforme is a skin condition of unknown etiology, but some authors suggest that the disease is mediated by deposition of immune complex ( mostly IgM ) in the superficial microvasculature of the skin and oral mucous membrane that usually follows an antecedent infection or drug exposure. It varies from a mild, self-limited rash (E. multiforme minor) to a severe, life-threatening form (E. multiforme major, or Stevens-Johnson syndrome) that also involves mucous membranes.

The skin form of E. multiforme, far more common than the severe form, usually presents with mildly itchy, pink-red blotches, symmetrically arranged and starting on the extremities. It often takes on the classical "target lesion" appearance, with a pink-red ring around a pale center. Resolution within 7-10 days is the norm.

The most common predisposing infection is Herpes simplex, but bacterial infections (commonly Mycoplasma) and fungal diseases are also implicated. E. multiforme may also be caused by drug reactions, most commonly sulfa drugs, phenytoin, barbiturates, penicillin, and allopurinol, or a host of internal ailments. The human form of Orf can also cause Erythema Multiforme.