Polymorphisms in HLA class II genes have been shown to contribute to susceptibility or protection against insulin-dependent diabetes mellitus (IDDM). In the present study the role of HLA class II haplotypes and the role of DQ alpha Arg52, DQ beta Asp57 and of polymorphic amino acids, located in the antigen-binding groove and the CD4-binding domain of the DR beta 1 chain, were studied in 210 unrelated Caucasian IDDM patients and 205 controls. The results showed that the genotype homozygous for DR beta 1Lys71+, which is in linkage disequilibrium with DQ alpha 1Arg52+ provided a major risk (relative risk, RR = 15.46) for IDDM and that combination of DR beta 1Lys71+/+ with homozygosity for DQ beta qAsp57-/- of the DQ beta 1 chain significantly increased the RR for developing IDDM (RR = 20.41). The DQ alpha 1Arg52(-)-DQ beta 1Asp57+ haplotype in cis or trans position conferred the highest protection against IDDM (RR = 0.08). Our findings confirm that protection against IDDM is provided by HLA-DQ loci but that susceptibility for IDDM is provided by both HLA-DRB1 and DQB1 loci. Our results also provide a new and more specific approach to determine the risk of any random Caucasian individual to develop IDDM. Indeed, increased susceptibility or protection against IDDM can be determined by the rapid and simple typing of DR beta 1Lys71, DQ alpha 1Arg52 and DQ beta 1Asp57 in a random person.