We studied the genetic markers in human leukocyte antigen (HLA) region HLA-A, -B, -C, -DR, -DQ, C2, Bf, C4A, and C4B of 31 patients with erythema multiforme (EM) and their families. In contrast to the complement allotypes, which showed no deviation from the distribution in the normal population, two HLA class II antigens occurred in much higher frequency in patients with EM. The frequency of HLA-DQw3 (77.4%) increased with high significance compared with normal Caucasian control individuals (41.2%). An even stronger DQw3 association was found in the patient group with postherpetic EM (88.8%; relative risk, 9.41). Interestingly, all patients suffering from frequently recurrent EM were found to have the DQw3 allele (relative risk 44.2). The previously reported association to HLA-B15 was also seen and may be due to a linkage disequilibrium with the HLA-DR4 allele (66.6% in recurrent EM). Our data provide further evidence that classic recurrent EM is related to herpes simplex virus infection and should be regarded as a distinct entity within the enigmatic EM syndrome. DQw3 may serve as a helpful marker for distinguishing this entity from other diseases with EM-like lesions.