Tumor necrosis factor (TNF)-alpha and TNF-beta, mediators of inflammatory responses, have been implicated in the pathogenesis of autoimmune diseases. The aim of this investigation was to determine whether two promoter region polymorphisms of the TNF-alpha gene (TNF-alpha -308 and TNF-alpha -238) and a determinant in the first intron of the TNF-beta gene (TNF-beta +252) affect susceptibility to systemic sclerosis (scleroderma) (SSc). Fifty patients and 60 healthy blood donors from Japan were genotyped for these markers by polymerase chain reaction-based methods. Fisher's exact test was used to test for significant associations. Because of very limited variation at the TNF-alpha -308 and TNF-alpha -238 loci in the Japanese people, statistical analyses with sufficient power could not be done for these genotypes. However, the two homozygous genotypes of the TNF-beta +252 locus were found to be significantly associated with SSc. Compared to controls, the frequency of the TNF-1 genotype was decreased, whereas that of TNF-2 was increased in SSc patients. The former implies an association with resistance, while the latter suggests an association with susceptibility to the disease. These results show that the TNF-beta +252 locus plays an important role in the etiopathogenesis of SSc.