Investigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case-control studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and case-control studies investigating the association between MTHFR C677T gene polymorphism and DN were included in the meta-analysis. The meta-analysis included 15 studies, of which 8 involved Caucasians and 5 East Asians; 11 studies involved subjects with type 2 diabetes and 4 with type 1 diabetes. The main analysis (all studies) revealed significant heterogeneity between the studies (P(Q)<0.01) and a marginal association between the 677T allele and the risk of developing DN; the random effects (RE) pooled odds ratio (OR) was 1.30 (1.03-1.64). However, the sensitivity analysis (exclusion of studies not in Hardy-Weinberg equilibrium) produced non-significant results. The recessive model derived significant results in main analysis [fixed effects (FE) OR=1.32 (1.10-1.58), P(Q)=0.27], and in type 2 diabetes [FE OR=1.30 (1.06-1.60), P(Q)=0.38]. The additive model produced significant association in main analysis [RE OR=1.65 (1.13-2.42), P(Q)<0.01] in Caucasians [FE OR=1.48 (1.11-1.98), P(Q)=0.17] and in type 2 diabetes [RE OR=1.65 (1.03-2.67), P(Q)<0.01]. However, sensitivity analysis diminished the significant results in type 2 diabetes. There is no differential magnitude of effect in large versus small studies. In conclusion, although there is some evidence of association between MTHFR C677T gene polymorphism and DN, the above findings reinforce the need for further and more rigorous association studies.