A significant increase in the frequency of DPw3/6 alleles defined by restriction-fragment-length polymorphism is observed in insulin-dependent diabetes mellitus (IDDM) patients relative to healthy control subjects (34.6 vs. 10.5%, P less than 0.009). Log-linear modeling demonstrates that this association is independent of HLA-DR3 and -DR4 and IDDM association and cannot be attributed to linkage disequilibrium between HLA-DP and -DR. The analysis also demonstrates an absence of interactive effects among the antigens in conferring IDDM susceptibility. The strength of the DPw3/6 association is not significantly less than that of either DR3 or DR4.