Plasma homocysteine (Hcy) concentration has been shown to be influenced by a mutation in the gene coding methylenetetrahydrofolate reductase (MTHFR). Although plasma Hcy has been shown to be related to atherosclerotic disorders, the association between MTHFR gene polymorphism and ischemic stroke remains controversial. In the present study we investigated the association between MTHFR gene polymorphism and risk factor-dependent augmentation for ischemic stroke in subjects with several risk factors for atherosclerosis, with special emphasis on the risk factor-gene interaction. The diagnosis of cerebral infarction in each patient was confirmed by computed tomography (CT) findings of the brain. MTHFR C677T polymorphism was genotyped with a conventional method. In 97 stroke patients (48 cases of atherothrombotic infarction, 38 cases of lacunar infarction, 9 cases of cardiac embolism, 2 others) and 241 age-and sex-matched healthy control subjects, the frequencies of the T allele were 0.44 and 0.39, respectively. In patients with CT-proven atherothrombotic infarction, the T allele frequency was 0.54 (P = .033 vs controls). The adjusted odds ratio in subjects with TT genotype for atherothrombotic infarction was 3.87 (95% confidence interval = 1.27-11.8). A general linear model analysis showed that an interaction between the HDL-C and MTHFR genotype was significantly associated with atherothrombotic infarction (F = 5.695; P = .018). These findings indicate that the T allele of the MTHFR gene is significantly associated with atherothrombotic infarction. Furthermore, the analysis of risk factor-gene interaction could be a useful tool for deriving specific predictive information about ischemic stroke in an elderly Japanese population.