In a study designed to evaluate the concept of inherited susceptibility to sarcoidosis, 73 patients with histologically proved chronic disease of sarcoid lung fibrosis (group 1) underwent typing of HLA-A, -B, -C and -DR antigens. Tests on 156 antiserum samples comprising 52 antigens of A, B, and C loci and on 35 comprising seven DR antigens on the surface of B cells were performed by means of the microdoplet assay of human serum cytotoxins. Two race-matched control groups consisted of 37 patients with lung fibrosis due to chronic extrinsic allergic alveolitis (group 2) and 162 healthy volunteers (group 3). The study further included a kinship with progressive sarcoidosis. The frequency of HLA-DR5 was significantly increased only in group 1 (relative risk, 6.6). HLA-DR5 was found in 38 patients (52%) in group 1, compared with five (14%) in group 2 and 23 (14%) in group 3. In the one family studied, HLA-DR5 was present only in one member, who had sarcoidosis. This study supports the hypothesis that the role of an infectious agent triggering sarcoidosis cannot be envisaged without considering genetically linked cofactors.