In 1982 we reported that among Caucasians with systemic lupus erythematosus (SLE) there is an increased frequency of C4A null. As this allele occurs on the HLA-A1,B8,BfS, C4AQO,B1,DR3 (8.1) supratype, we suggested this accounted for the reported association of B8 and DR3. Since then we have shown that many supratypes including 8.1 identify unique segments of DNA conserved from a common but remote ancestor. Many of these ancestral haplotypes (AH), including 8.1, carry disease genes and some bear C4 null. We have therefore tested the hypothesis that in SLE C4 null alleles are directly involved by examining (1) whether all or only some AH bearing C4 null alleles are increased, (2) whether C4 null is increased in all racial groups examined, and (3) whether C4 null is associated with the presence of antinuclear antibodies (ANA) in the absence of SLE. We performed HLA and complement allotyping on 62 Australian Caucasians and 9 Australian aborigines with SLE and on the 10 out of 133 healthy individuals with 7 or more international units of ANA. Our data confirm an association of C4A null in Australian Caucasians (gene frequency 0.30 versus 0.15 in controls) and show an increased frequency of C4B null in Australian aborigines (gene frequency 0.33 versus 0.22). A review of an extensive literature shows C4A and/or C4B null are increased in all racial groups examined. On the other hand, the HLA-A3,B7,BfS,C4A3,B1,DR2 (7.1) AH rather than C4 null is associated with ANA in health. Our data indicate that while C4 nulls contribute to MHC susceptibility, other genes are likely to be involved.