Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme of folate/homocysteine metabolic pathway. C677T polymorphism of MTHFR gene was reported as risk factor for congenital defects, metabolic and neuropsychiatric disorders. Numerous case-control studies investigated C677T polymorphism as risk factor for schizophrenia but results of these studies were contradictory. To draw a conclusion, a meta-analysis of all available case-control studies was performed. PubMed, Google Scholar, Springer Link and Elsevier databases were searched for eligible case-control studies. Pooled odds ratio with 95%CI was used as an association measure and all statistical analyses were performed by Open Meta-Analyst and MIX software. Total 38 studies with 10,069 cases and 13,372 controls were included in the present meta-analysis. Results of meta-analysis showed significant associated between C677T polymorphism and risk of schizophrenia (ORTvsC = 1.18, 95%CI = 1.10–1.27, p = < 0.001; ORCTvsCC = 1.10, 95%CI = 1.04–1.17, p = <0.001; ORTTvsCC = 1.40, 95%CI = 1.20–1.64, p = <0.001; ORTT+CTvsCC = 1.19, 95%CI = 1.09–1.30, p = <0.001). We also performed subgroup and sensitivity analyses. Subgroup analysis was done according to ethnicity and significant association was found between C677T polymorphism and risk of schizophrenia in all three ethnic populations—African (OR = 2.51; 95%CI = 1.86–3.40; p = <0.001), Asian (OR = 1.21; 95%CI = 1.10–1.33; p = <0.001) and Caucasian (OR = 1.07; 95%CI = 1.01–1.14; p = 0.01). In conclusion the results of the present meta-analysis suggested that the MTHFR C677T polymorphism is a risk factor for schizophrenia.