Thirty patients with systemic sclerosis (scleroderma) and 188 healthy controls were studied for class I and class II MHC antigens. All patients with scleroderma fulfilled the ARA preliminary criteria for systemic sclerosis. The frequencies of HLA antigens B8, DR3 and DR52 were higher in patients with scleroderma as compared with controls. Ten patients had anti-Scl-70 antibodies, and four of them (40%) had HLA-DR5 antigen compared to 19 of 188 controls (10%), P = 0.013. The relative risk for DR5 in anti-Scl-70-positive patients was 3.6 compared to 1.6 of DQ3 suggesting the primary significance of DR5 compared to DQ related factors. Patients with neurological manifestations had higher frequencies of B8 and DR3 than those with no neurological manifestations of scleroderma. Our results support the view that immunogenetic background is associated with different clinical subsets of systemic sclerosis.