Recent studies indicate that the susceptibility to various inflammatory rheumatic diseases is an inherited trait determined by gene products of the class II histocompatibility complex (HLA-DR determinants). In a study designed to evaluate the concept of inherited susceptibility to sarcoid arthritis (SA), 42 patients with histologically proved acute disease underwent typing of HLA-A, -B, -C and -DR antigens. Using the microdroplet assay of human serum cytotoxins, we employed 156 antiserums to identify 52 antigens on A, B and C loci and 35 to identify 7 DR antigens on the surface of B cells. An ethnically matched control group consisted of 134 healthy volunteers. The frequency of B cell isoantigen DR3 specificity was significantly increased in patients with SA (relative risk, 4.8); HLA-DR3 was found in 25 (60%) of the patients, compared with 31 (23%) of the controls. This study lends further support to the hypothesis that the putative role of an infectious agent triggering SA cannot be judged without considering genetic cofactors.