Moderately elevated plasma homocysteine levels have been established as independent risk factors in vascular disease, including ischemic stroke. Recently, a common mutation (C677T) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene reducing the activity of MTHFR and increasing homocysteine levels in plasma was reported. The C677T MTHFR mutation may be a risk factor for ischemic stroke, but the results of previous studies have been conflicting. One possible explanation is that the association with the MTHFR genotype may be different according to gender. To investigate the association for ischemic stroke, we conducted a case-control study of 77 hospital cases (49 men and 28 women) with ischemic stroke and 229 (120 men and 109 women) control subjects in Japanese. The prevalence of conventional vascular risk factors and MTHFR genotypes were determined in case and controls. After adjustment by multiple analysis in all there was no statistical significance in MTHFR genotypes. The conventional vascular risk factors such as diabetes mellitus (adjusted odds ratio [OR], 17.21), hypertension (adjusted OR, 4.67), smoking habit (adjusted OR, 4.70), and hyperlipidemia (adjusted OR, 2.73) were identified independently associated with ischemic stroke. With a separate sex analysis it was identified that the relationship of the MTHFR T/T gneotype was statisticaly significant in women (adjusted OR, 9.49; 95% CI, 1.75-51.47, P=0.0091). The relevance of the MTHFR T/T mutation appears to be restricted to women, suggesting a role of female hormones in the resistance to elevated homocysteine levels due to the MTHFR T/T mutation.