In a prospective clinical study of erythema multiforme (EM), we identified 22 subjects who experienced more than 1 episode. These subjects were young, with an average age of 29 years. They had an average number of 12 previous episodes, with each episode lasting 3 weeks. The average interval between episodes was 4.9 months. We counted the number and location of each skin lesion and found that patients had an average of 188 EM skin lesions at the time of their evaluation. We found the isomorphic phenomenon, that is, lesions appearing at sites of skin trauma, in 19 of the 22 study subjects; photodistribution of skin lesions in 15 of the 22, grouping of the lesions over the elbow and knees in 7 of the 22, and nailfold involvement in 7 of the 22. In this study there was compelling evidence for herpes simplex virus association with recurrent EM. All 22 patients had histories of herpes simplex virus infections preceding at least 1 of their previous episodes of EM. Sera from all study subjects had antibodies to HSV detectable by enzyme immunoassay. None, however, had HSV isolated from the throat at the time of the EM or from an EM skin lesion. All 11 patients who were subsequently tested had positive viral cultures for HSV taken from the suspected recurrent herpes lesion. When 8 EM skin biopsies were examined by indirect immunofluorescence with a monoclonal antibody to the type common HSV glycoprotein gB, all had positive staining of keratinocytes. Only one-third of patients with a single episode of EM had a history of possible herpes lesions preceding EM.(ABSTRACT TRUNCATED AT 250 WORDS)