Immunogenetic markers, autoantibodies, and clinical features were studied in 47 patients, 35 Caucasian and 12 black, with systemic sclerosis. Twenty-two had generalized scleroderma, while 25 had limited skin involvement. HLA-DR1 (RR = 2.1, p = 0.08) and DR5 (RR = 2.1, p = 0.08) were increased in Caucasian patients vs controls as was the supertypic specificity HLA-DRw52 (RR = 2.8, p = 0.02, pc = 0.04). HLA-DR6.1 was increased in black patients vs controls (RR = 15.4, p = 0.008, pc = 0.088). There were no significant increases in any of the complement allotypes in either racial group. Anticentromere antibody was noted in 10 patients, all Caucasian; 7 had limited disease. Anti-Scl-70 was noted in 4 patients; all had generalized disease (p = 0.036). HLA-DR2 was present in all anti-Scl-70 positive patients (RR = 22.5, p = 0.006). Our results suggest that clinical subsets of systemic sclerosis can be defined by genetic and serological markers.