Twelve family members of a patient with systemic lupus erythematosus (SLE) and heterozygous deficiency of the second component of complement (C2) were studied. Histocompatibility (HLA) typing was determined for A, B, and DR and MB antigens. Serum samples were tested for a variety of antinuclear antibodies (ANA), lymphocytotoxic antibodies and rheumatoid factors, and C2 levels were determined by hemolytic titration. Inheritance of C2D, the gene coding for C2, was limited to the haplotype HLA-A25, B18, DR2. Low but significant titers of ANA, rheumatoid arthritis nuclear antigen (RANA) and/or rheumatoid factors were found in eight of the nine adult family members without association with HLA haplotype. The sister of the proband had persistently strongly positive LE cell preparations for more than a decade and had joint pains while taking sulfa drugs. The son of the proband had leukemia. All other family members were healthy. We conclude that the increased incidence of rheumatic disease in persons with C2D deficiency is multifactorial and requires environmental factors or other hereditary factors unrelated to the HLA-A25, B18, DR2 haplotype. The C2D gene is clearly not associated with positive ANA tests or immunoprecipitins to RANA.