Methylenetetrahydrofolate reductase (MTHFR) is involved in the homocysteine metabolism. Two common variants of MTHFR gene (677C>T and 1298A>C), have been reported to reduce the MTHFR enzyme activity and leading to plasma hyperhomocysteinemia. There are a number of recent case-control studies that investigated the association between the MTHFR polymorphism and diabetic nephropathy (DN), albeit with inconsistent results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of MTHFR with susceptibility to DN. A literature search was conducted on PubMed, Embase and Google scholar from inception till March 18, 2019. For MTHFR 677C>T analysis, a total of 23 studies including DM controls (3095 cases and 3187 DM controls) and 12 studies including non-DM controls (1590 cases and 2052 nonDM controls) were taken. For MTHFR 1298A>C analysis, a total of 7 studies using DM controls (959 cases and 1209 DM controls) and 3 studies using non-DM controls (400 cases and 802 nonDM controls) were taken. Meta-analysis showed that mutant genotypes of the 677C>T (OR: 1.58; 95%CI: 1.16-2.14) and 1298A>C (OR: 1.38; 95%CI: 1.16-1.65) polymorphisms in the MTHFR gene were associated with increased risk of DN (diabetic kidney disease). MTHFR 677C>T and 1298A>C polymorphisms revealed significant heterogeneity between studies. Further, there was no evidence for publication bias for these polymorphisms. In conclusion, this meta-analysis provides strong evidence that MTHFR 677C>T and 1298A>C polymorphisms may be associated with increased risks of DN. However, further studies are still needed to accurately determine whether MTHFR genetic polymorphisms are associated with susceptibility to DN.