This study was designed to test the hypothesis that genotypic changes of tumor necrosis factor alpha (TNF-alpha) promoter region are associated with endometrial cancer. TNF-alpha gene encodes a cytokine involved in angiogenesis and oncogenesis of several cancers. Some uncommon alleles are reported to be associated with increased production of TNF-alpha and the onset of various cancers. Studies of such alleles are lacking in endometrial cancer. In this study, we examined the genetic changes at the polymorphic 3 loci of TNF-alpha promoter regions (-238, -308 and 488) in 41 Japanese patients with uterine endometrial carcinomas (UEC). Nine of 41 UEC samples (22%) had genotype changes from GA to A at -308 promoter region of the TNF-alpha gene. There were no genotype changes at -238 and 488 regions of TNF-alpha in UEC samples. The results of our study demonstrate for the first time that genotype changes from GA to A in UEC patients. We conclude that the genotype changes at -308 promoter region of TNF-alpha may play an essential role in the malignant transformation of endometrial cells.