Background: To evaluate the role of plasma total homocysteine (tHcy) and homozygosity for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) C677T genotype in the risk of retinal vein occlusion (RVO). Methods: Relevant studies were selected through an extensive search of PubMed, EMBASE, and the Web of Science databases. Summary weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CI) were calculated with a random-effects model. Results: Forty-two studies with 6445 participants were included in this updated systematic review and meta-analysis. The mean plasma tHcy level in the RVO patients was significantly higher than in the controls (WMD = 2.13 mu mol/L; 95% CI: 1.29 to 2.98, P < 0.001), but there was evidence of between-study heterogeneity (P < 0.001). No significant association between MTHFR C677T genotype and RVO was found under all genetic models. Conclusion: There was some evidence that plasma tHcy is associated with an increased risk of RVO. There was no evidence to suggest an association between homozygosity for the MTHFR C677T genotype and RVO.