The HLA genotype DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 confers a 25-fold increase in the risk of type 1 diabetes. In persons with this genotype, DRB1*0405, *0402, and *0401 subtypes have been reported to further increase risk, whereas the *0403 and *0406 alleles confer a relative protection. We compared the frequencies of the DRB1*04 alleles in 193 type 1 diabetic patients with the HLA-DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 genotype (140 non-Hispanic white [NHW] and 53 Hispanic) and 205 nondiabetic controls (142 NHW and 63 Hispanic). In addition, 87 NHW first-degree relatives of type 1 diabetes patients were studied: 33 positive and 54 negative for autoantibodies to insulin, GAD65, or IA-2. The HLA-DRB1 was typed using standard PCR SSOP methods. DRB1*0401 (OR, 2.19; 95% CI, 1.36-3.54) in NHW and *0405 (OR, 3.78; 95% CI, 1.43-10.0) in Hispanics were significantly associated with T1DM, whereas DRB1*0403 was protective (OR, 0.19; 95% CI, 0.04-0.89 in NHWs; OR, 0.10; 95% CI, 0.01-0.83 in Hispanics). Associations between the DRB1*04 alleles and prediabetic islet autoimmunity were generally in the same direction as those with diabetes. Among diabetic patients, the mean age of diagnosis appeared to be higher among those with the *0403 and *0407 allele compared with the others. In summary, on the DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 genotypes, the *0403 allele confers relative protection from type 1 diabetes and development of islet autoantibodies in both Hispanics and NHWs and is associated with older age at diabetes diagnosis. Although the associations between diabetes and *0401 and *0405 appear to differ somewhat between Hispanics and NHWs, overall there is no significant difference between these two ethnic groups.