The contribution of SNPs in TNF genes to type 1 diabetes (T1D) is not well established and may be confounded by the linkage disequilibrium within the HLA genes. Seven SNPs in the TNF genes (TNFA and TNFB) were genotyped in a Korean cohort (398 T1D patients and 1422 nondiabetic controls), along with HLA DRB1, DQB1, and MICA (MHC class I chain-related genes). Among them, three SNPs (TNFB+318, TNFA-857, and TNFA-308) and two common TNF haplotypes showed significant association with the risk of T1D (P= 5 x 10(-3)-10(-5)). T1D patients were more often heterozygous for the alleles at the TNFB+318 (OR = 1.7, P= 10(-3)) and TNFA-308 (OR = 1.7, P < 10(-5)) than were the controls. Genetic association analyses of the DRB1, DQB1, and MICA alleles with the risk of T1D revealed dramatic associations in several alleles as expected. Independent analyses to discern the genetic effects of TNF polymorphisms on the risk of T1D suggested that these genetic influences might be not totally dependent on the nearby HLA genes. Our results support the hypothesis that two susceptibility loci in the MHC (one in the HLA class II and another in the central MHC region) act epistatically to increase susceptibility to T1D.