The relationship between HLA-DR antigens and various specific antinuclear antibodies was studied in 28 unselected black Americans with systemic lupus erythematosus (SLE). Anti-SSA(Ro) occurred with high frequency (61%) but was not associated with specific clinical features of SLE. HLA-DR7 was strongly associated with anti-SSA antibody; it was present in 13/17 patients with anti-SSA (76%) and 1/11 patients without it (9%). HLA-DR7 occurred in 14/28 of all SLE patients (50%) compared with 17% of 137 local controls (p corrected, less than 0.005). This association of HLA-DR7 with both susceptibility to SLE and a high frequency of anti-SSA antibody suggests a genetic link between the presence of anti-SSA antibody and susceptibility to SLE in the population studied.