Genetic factors predisposing to autoimmune diseases were investigated in 10 families having more than one affected member. Seventy relatives and 23 spouses from two large kindreds (one in whom the proband had autoimmune hemolytic anemia and the other immune thrombocytopenic purpura) were examined for immunologically mediated disorders, autoantibodies, immunoglobulin abnormalities, and HLA genotypes. Significant differences between relatives and spouses were found for immune diseases (21 percent versus 0 percent; p = 0.02), antinuclear antibody titer of 1:80 or more (18 percent versus 0 percent; p = 0.04), single-strand DNA antibodies (18 percent versus 0 percent; p = 0.04), high-titer antinuclear antibody or antibodies to single-strand DNA or both (33 percent versus 0 percent; p = 0.001), and the combined frequencies of immune diseases and serologic abnormalities (44 percent versus 4 percent; p = 0.0004). Similar frequencies were found in 41 relatives from eight families in whom the proband had SLE. Segregation analyses using these abnormalities as genetic traits were most compatible with a Mendelian dominant model. Impressive odds (100:1) against linkage to HLA were calculated.