The families of 41 probands with type I (insulin-dependent) diabetes mellitus (IDDM) were typed for HLAA, HLA-B, and HLA-DR antigens in addition to the complement polymorphisms C2, C4A, C4B, and Bf. All of these loci are encoded on the short arm of human chromosome 6 in a narrow region. Alleles at HLA-B (8, 15, 18, and 40), HLA-DR (3 and 4), and Bf (F1) have been associated with increased relative risk (RR) for IDDM, while HLA-B7 and HLA-DR2 have been associated with decreased RR for IDDM. This study confirms those significant risks in addition to confirming increased risk for the null (silent) allele for C4A (C4AQ0) and a rare C4B variant (C4B2.9). The significantly associated antigens (alleles) and risks were: HLA-B8 (RR = 3.1), HLA-DR3 (RR = 5.2), HLA-DR4 (RR = 4.3), and BfF1 (RR = 7.1), in addition to C4AQ0 (RR = 2.8) and C4B2.9 (RR = 12.6). Significantly low risk was associated only with HLA-DR2 (RR = 0.1). In a recent study, we defined five high-risk haplotypes that were determined solely by HLA-B, Bf, and HLA-DR (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4). By inclusion of information from the complement polymorphism, we have defined in greater detail three of these five high-risk haplotypes. One previously identified haplotype (B40-BfS-DR4) showed no complement clustering, while the rare high-risk haplotype (B8-BfS-DR4) was seen only once in this smaller sample. Information at the HLA-A locus was deemed important only in the definition of the B8-BfS-DR3 extended high-risk haplotype. Three haplotypes that exhibited significantly increased risks with complement inclusion were B8-BfS-C2C-C4AQ0-C4B1-DR3 (RR = 2.4), B15-BfS-C2C-C4A3-C4B2.9-DR4 (RR = 10.2), and B18-BfF1-C2C-C4A3-C4BQ0-DR3 (RR = 10.6). Of possibly major significance, it was shown that all probands carried at least one high-risk antigen or allele.