The role of the DPB1 gene in genetic susceptibility to type I diabetes has yet to be elucidated. Studies of DPB1 alleles are conflicting. Analysis at the amino acid level, rather than consideration of allelic polymorphism, has been informative in determining disease susceptibility encoded by the DRB1 and DQ genes. In this study, therefore, amino acid variation at polymorphic sites of the DPbeta peptide chain encoded by the second exon of the DPB1 gene was analyzed in diabetic and control subjects from white Caucasian, North Indian Asian, and Jamaican populations. Human leukocyte antigen genotypes and haplotypes were analyzed using a logistic-regression approach and the data were conditioned for the effects on disease risk of the DRB1, DQA1, and DQB1 genes. Eight DPbeta amino acid residues were significantly associated with type I diabetes independent of DR and DQ (DPbeta 9, 33, 35, 36, 55, 56, 57, and 69). None of these residues, however, correlated consistently with disease risk in all three racial groups. This contrasts with findings for the DRbeta, DQalpha and DQbeta peptide chains, where the identity of the amino acid at particular sites has been found to correlate with predisposition to type I diabetes.