Systemic lupus erythematosus is a disease characterized by several immunologic abnormalities. We determined the HL-A antigens of 40 patients by a standard lymphocyte cytotoxicity test. Specificity HL-A8 was present in 33 per cent, and W15 (LND) in 40 per cent of the patients, as compared to control population frequencies of 16 per cent (p less than 0.025) and 10 per cent (p less than 0.0005), respectively. Nineteen other HL-A antigens did not differ significantly between patients and the control population, and no unusually frequent phenotypes were observed. The association between histocompatibility loci and susceptibility to certain diseases may be mediated by histocompatibility-linked immune response genes analogous to such associations demonstrated in mice. Other possible mechanisms for this association are that histocompatibility antigens represent specific receptor sites for attachment of a virus and that "cross-tolerance" enables viral antigens to mimic certain histocompatibility antigens.