The distribution of HLA class II alleles and genotypes in IDDM patients was examined in the three main Israeli ethnic groups: Ashkenazi Jews, non-Ashkenazi Jews, and Arabs. Molecular sequence specific oligonucleotide probe analysis was performed for DRB1, DQA1, and DQB1 genes. The DRB1*03011, DQA1*05 DQB1*02/DRB1*0402, DQA1*03, DQB1*0302 genotype was found to be the main susceptibility genotype in all three groups, with differences in the degree of association. In addition to DRB1*0402 (more frequent among Ashkenazi Jews), DRB1*0405, another subtype of DRB1*04, was found to be more prevalent among non-Ashkenazi Jews and Arabs. Many alleles were found to be negatively associated with insulin dependent diabetes mellitus (IDDM). This could be a result of the high frequency of susceptible alleles, or of linkage disequilibrium to a primary negatively associated allele. The strongest negative association was observed for DQB1*0301 in all three ethnic groups. The alleles DRB1*1401, DRB1*1501, DQB1*05031, DQB1*0602, and DQB1*0609 were not detected in any of the 202 IDDM patients, and are probably either strongly protective or in linkage with such alleles. Despite the differences found between the three ethnic groups, an overall analysis shows that the DRB1*04 alleles that account for susceptibility to IDDM in the Israeli population (DRB1*0402 and *0405) are the same as those responsible for susceptibility to IDDM in a number of other Mediterranean populations. In contrast, the susceptible allele in most Caucasian populations is DRB1*0401. It is noteworthy that the susceptible alleles DRB1*0402/05 for Mediterranean and DRB1*0401 for Caucasian populations are also frequent in the respective healthy populations. These findings support the results obtained in other studies, which point to a genetic relationship between the Israeli and Mediterranean populations.