Abstract Background Previous studies concerning the association between the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and depression have provided inconclusive findings. A meta-analysis was therefore performed to investigate a more reliable estimate. Methods This meta-analysis recruited 26 published studies which were selected by a search of electronic databases up to January 2013, including 4992 depression cases and 17,082 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR C677T polymorphism and depression susceptibility using random effect models. Results Meta-analyses results suggested that MTHFR C677T polymorphism contributed to the increased depression risk in overall populations (for T vs. C: OR=1.19, 95%CI=1.07–1.32; for TT+CT vs. CC: OR=1.15, 95%CI=1.01–1.31; for TT vs. CC: OR=1.42, 95%CI=1.16–1.75; for TT vs. CT+CC: OR=1.38, 95%CI=1.16–1.63). Subgroup analysis by ethnicity indicated an association in Asian populations (for T vs. C: OR=1.36, 95%CI=1.11–1.66; for TT+CT vs. CC: OR=1.32, 95%CI=1.03–1.69; for TT vs. CC: OR=1.88, 95%CI=1.26–2.79; for TT vs. CT+CC: OR=1.76, 95%CI=1.30–2.38); and a marginal association in White populations (for TT vs. CT+CC: OR=1.15, 95%CI=1.01–1.31). However, the association between the MTHFR C677T polymorphism and depression was not observed in the elderly. Conclusion The MTHFR C677T polymorphism was associated with an increased risk of depression, especially in Asian populations. However, there was no evidence indicating a correlation in the elderly.