The cause of vulvar lichen sclerosus (VLS) is unknown. An autoimmune origin has been suggested. The HLA system is responsible for the synthesis of major histocompatibility antigens and is considered a genetic marker of the risk of or resistance to some diseases. Recently, the association between some antigens of the HLA system and diseases of proven autoimmune origin has been reported. A possible association between antigens of the HLA system and VLS has been investigated by others, with contradictory results. Here we report the results of HLA typing in 68 women with histologically proven VLS. The following antigens were tested: A1, A2, A3, A9-11, A28, A29, A32, B5, B7, B8, B12-B18, B21, B22, B27, B35, B40, Cw1-4, Dr1-5 and Dr7. The results were compared with the frequency of HLA antigens in about 2,000 controls. Patients affected by VLS showed an increased frequency of HLA-B21 (22.06% vs. 9.56%, P less than .001), HLA-Dr5 (55.38% vs. 40.92%, P less than .025) and HLA-Dr7 (38.46% vs. 25.19%, P less than .025). After correction for the number of antigens tested (44) the difference in HLA-B21 frequency was significant at the P less than .05 level. This finding gives further support to the suggestion that an immune system disorder is involved in the origin of VLS.