The human leukocyte antigen (HLA) class II DQB1*0201/0202-DRB1*04 genotype has been identified as predisposing to type 1 diabetes [insulin-dependent diabetes mellitus (IDDM)] in the Saudi Arabian population (P = 0.0002; odds ratio = 0.67; 95% confidence interval = 0.009-0.381). In this study, we searched for a factor at the DPB1 locus by analysing DPB1 polymorphism using sequence-based typing in 86 Saudi IDDM patients and control subjects, all carrying the HLA-DRB1*04/DQB1*02 haplotype or the known susceptibility allele DQB1*0201/0202. Significant protection was conferred by DPB1*0401, which was observed in 17 of 50 control subjects (55%) and 2 of 36 IDDM patients (5%) with the DQB1*0201/0202 allele (P = 0.0012; odds ratio = 8.75; confidence interval = 1.72-59.70). Our data showing a high frequency of the DPB1*0401 allele even in the presence of the predisposing DQB1*02 allele in healthy subjects may indicate a protective effect of this combination of HLA alleles against type 1 diabetes. This finding supports the hypothesis that protective HLA class II genes can override the risk conferred by HLA-DQ susceptibility alleles. Further studies using larger cohorts of control subjects and patients should be undertaken to confirm this observation.