HLA-DRB1 and -DQB1 genes were analyzed in 98 Chinese IDDM patients and 205 control subjects from Taiwan. The DRB1*0301-DQB1*0201 haplotype conferred strong susceptibility (RR = 7.7, pc < 10(-5)). DRB1*0405 also conferred susceptibility (RR = 3.1, Pc < 0.0005) whereas DRB1*0403 (RR = 0.7) and DRB1*0406 (RR = 0.2) conferred protection. Indeed, the relative risk for the DRB1*0405-DQB1*0302 haplotype (RR = 33.7, Pc < 0.002) was 48 and 168 times higher than those conferred by the DRB1*0403-DQB1*0302 and DRB1*0406-DQB1*0302 haplotypes, respectively, suggesting that the protection conferred by DRB1*0403 and 0406 is dominant over DQB1*0302. The strong linkage disequilibrium observed between DQB1*0302 and DRB1*0403(0406) can thus explain the surprising finding that the frequency of DQB1*0302 was not significantly increased in the Chinese IDDM patients (RR = 0.9). Because the DRB1*0405-DQB1*0302 haplotype (RR = 33.7) conferred higher susceptibility than the DRB1*0405-DQB1*0401 (RR = 2.5) or DRB1*0405-DQB1*0301 (RR = 2.1) haplotypes, DQB1*0302 is indeed a susceptibility factor, while both DQB1*0301 and DQB1*0401 may confer protection against IDDM. The increased frequency of the protective DQB1*0401 allele in patients compared to controls is due to linkage disequilibrium between DRB1*0405 and DQB1*0401. Interestingly, the previously demonstrated protective effect of DQB1*0602 was not very strong in the Chinese (RR = 0.4). Our results suggested that HLA-encoded susceptibility to IDDM is determined by the combined effects of all DR and DQ molecules present in an individual. Therefore, the genotypic combinations of DR and DQ genes as well as their linkage disequilibria can influence IDDM susceptibility. At least four DR and DQ molecules conferring high susceptibility (DRB1*0301, DRB1*0405, and DQ alpha/beta 0301/0201 and 0301/0302) occur at high frequency in the Chinese population. However, linkage disequilibria between highly susceptible DR and protective DQ or vice versa (e.g., DRB1*0405-DQB1*0301[0401] and DRB1*0403[0406]-DQB1*0302) are probably responsible for the lower incidence of IDDM in the Chinese.