<i>Background and Purpose:</i> The aims of this study were to evaluate the role of tumor necrosis factor-α <i>(TNF-</i>α<i>)</i> polymorphisms in patients susceptible to ischemic stroke and silent brain infarction (SBI), and to determine the relationship between <i>TNF-</i>α polymorphisms and plasma total homocysteine (tHcy) levels. <i>Methods:</i> We studied 237 patients with ischemic stroke, 257 patients with SBIs, and 216 control subjects. For control subjects, we selected healthy individuals matched for gender and age from those individuals who came to our hospital for health examinations. The <i>TNF-</i>α–308G→A and –238G→A genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. <i>Results:</i> The frequency of the <i>TNF-</i>α–308G→A polymorphism was significantly different between the patients with ischemic stroke and the control group (GG vs. GA+AA; adjusted odds ratio, AOR, 0.50; 95% CI 0.255–0.989). By subgroup analysis, when tHcy levels were stratified into high (>10.80 µmol/l), moderate (8.21–10.80 µmol/l), and low levels (<8.21 µmol/l), the frequency of the <i>TNF-</i>α–308GA+AA genotype in the highest tertile group was higher than in the lowest tertile group (AOR 2.46; 95% CI 1.063–5.699). However, the relationship between SBI susceptibility and polymorphisms of <i>TNF-</i>αwas not established. The tHcy levels were significantly and inversely correlated with folate levels in the <i>TNF-</i>α–308GG and <i>TNF-</i>α–238GG genotypes in the ischemic stroke, SBI, and control groups (p< 0.05). <i>Conclusions:</i> Our results suggest that the <i>TNF-</i>α–308G→A polymorphism is responsible for susceptibility to ischemic stroke and is associated with high tHcy levels in Koreans.