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The molecular association of HLA class II with type 1 diabetes (T1DM) was investigated in Tunisian Arabs using 3 kinds of analyses. The first was a case-control association study, using Relative Predispositional Effects method, involved 137 T1DM cases and 258 control subjects. The second was family-based association-linkage study, using Transmission Disequilibrium Test, and covering 50 Tunisian families comprising 73 T1DM patients and 100 parents. The third was a wide correlation study between 4 DRB1 alleles (DRB1*03, *04, *11, *15) and T1DM in 52 countries, using Spearman’s Rho. Results from Case-control and family-based association studies showed that DRB1*03 and DRB1*04 alleles predispose to T1DM in Tunisian Arabs. Conversely, only DRB1*11 was protective for T1DM. DRB1*04-DQB1*03 haplotype was consistently associated positively with T1DM; DRB1*03/DRB1*04 genotype had the highest risk of T1DM development. Compared to DRB1*03, HLA-DRB1*04 was associated with higher T1DM incidence. Thus, the contribution of HLA class II to T1DM genetic susceptibility must be evaluated with regards to specific HLA alleles, genotypes, and haplotypes, and also ethnic and racial background.