AIM: To systematically understand the genetic association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and primary open angle glaucoma (POAG). METHODS: A comprehensive literature search in Google Scholar, PubMed, Science Citation Index, Foreign Medical Literature Retrieval Service, Chinese National Knowledge Infrastructure and Wanfang Databases was performed to collect all eligible studies up to August 2019. Study selection, data abstraction and study quality evaluation were performed by two independent investigators. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association. RESULTS: Eighteen case-control studies including 2156 cases and 2201 controls were identified. There was no significant difference in the terms of MTHFR C677T polymorphism and POAG in the Caucasian population (for T vs C OR=1.11, 95%CI: 0.88 to 1.39; for TT vs CC OR=1.01, 95%CI: 0.76 to 1.36; for TT+TC vs CC OR=1.15, 95%CI: 0.84 to 1.58 and for TT vs TC+CC OR=1.02, 95%CI: 0.78 to 1.33). However, a significant effect was revealed in the Asian population (for T vs C OR=1.34, 95%CI: 1.12 to 1.59; for TT+TC vs CC OR=1.41, 95%CI: 1.14 to 1.76). CONCLUSION: Based on 18 eligible studies, we provide a correlation between MTHFR C677T polymorphism and POAG among the Asians subgroup indicating that the T allele or TT +TC genotype may play a critical role in POAG development in Asians.