Background: Hyperhomocysteinemia, a condition that is strongly determined by dietary intake of B vitamins, has been suggested to be an independent risk factor for ischemic stroke (IS). To test this hypothesis, we performed a meta-analysis to investigate the associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, which plays a critical role in modulating plasma homocysteine concentrations, and IS risk. Materials and Methods: We searched case-control studies on the association between MTHFR C677T genetic polymorphism and susceptibility to IS through PubMed, Embase, and Medline databases from January 2000 up to October 2014. The random-effects model was employed because moderate heterogeneity across studies was observed, as assessed by I-2 statistic. Publication bias was estimated using funnel plot and Egger's regression test. Results: A total of 22 case-control studies were included in the current meta-analysis. Significant associations between MTHFR C677T genetic polymorphism and IS were found under the dominant model (pooled odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.24-1.57), the recessive model (pooled OR = 1.37, 95% CI: 1.16-1.61), and the allele model (pooled OR = 1.29, 95% CI: 1.18-1.42). Conclusions: The meta-analysis suggests that MTHFR C677T genetic polymorphism is significantly associated with susceptibility to IS, which provides evidence supporting hyperhomocysteinemia as a risk factor for stroke.