Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of atherosclerosis. Two biallelic polymorphisms in the TNF-alpha (TNF-alpha -308) and TNF-beta (TNF-beta +252) genes have been reported to be associated with TNF production and susceptibility to inflammatory diseases. We investigated two genetic polymorphisms in the TNF locus (TNF-alpha -308 G-->A and TNF-beta +252 A-->G) as risk factors for cerebral infarction (CI) by determining its prevalence in 294 survivors of CI, and in 581 age-, gender-, and race-matched controls. A significant association was found for the TNF-alpha and TNF-beta genotypes in CI patients compared with controls. A significant increase was found for the TNF-alpha A allele in controls compared with CI patients (chi2 = 7.593, p = 0.006, odds ratio = 1.74, confidence interval = 1.17-2.59). In addition, the TNF-alpha GG genotype increased the relative risk for CI in subjects with the TNF-beta AA genotype (chi2 = 4.998, p = 0.025). As a result, compared to controls, the frequency of the TNF-alpha AA genotype was decreased, whereas that of TNF-beta AA was increased in CI patients. The former implies an association with resistance, whereas the latter suggests an association with susceptibility to the disease. These results show that the TNF-alpha -308 and TNF-beta +252 locus plays an important role in the etiopathogenesis of CI.