To determine the contribution of the tumor necrosis factor alpha gene (TNFA) to the immunogenetic risk prediction of type 1 diabetes (T1D) in the Belgian population, well-characterized antibody-positive patients with type 1 diabetes (T1D), nondiabetic control subjects, and nuclear families were analyzed for HLA-DQA1-DQB1, TNFA -308 G/A promoter single nucleotide polymorphism (SNP) and TNFa microsatellite markers in both case-control and transmission studies. A total of 1,029 patients (mean age at onset, 18 years; male/female ratio, 1.2), 575 control subjects and 179 nuclear families were analyzed for the -308 SNP and 1,082 patients (mean age at onset, 17 years; and male/female ratio, 1.3), 606 control subjects, and 261 nuclear families were analyzed for the TNFa microsatellite marker. All subjects were typed initially for HLA-DQ. No primary association was detected with the -308 G/A promoter SNP. In contrast, we found evidence of a contribution of TNFa1 allele to susceptibility for T1D independently of HLA-DQ. We observed that the conserved HLA-DQ-TNFa extended haplotype, HLA-DQA1 0501-DQB1 0201-TNFa1 is a diabetogenic haplotype in the Belgian population and is independent of age at onset and gender and confers an estimated relative risk of 4.55 and an absolute risk of 1.7%. In conclusion, our observations suggest that the-308 G/A promoter SNP is not a genetic marker for T1D, but that the TNFa microsatellite may have an added value to further refine the immunogenetic risk conferred by the HLA-DQ region in the Belgian population.