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Insulin resistance plays a part in diabetic nephropathy (DN). The association between the peroxisome proliferator–activated receptor γ Pro to Ala alteration at codon 12 (Pro12Ala) polymorphism and the risk of insulin resistance has been confirmed. The association between the polymorphism and DN risk has also been widely studied recently, but no consensus was available up to now.A systematic search of electronic databases (MEDLINE, Embase, and China National Knowledge Infrastructure) and reference lists of relevant articles was carried out, and then 18 case-control studies involving 3,361 DN cases and 5,825 control subjects were identified.In the overall analysis, the Ala12 variant was observed to be significantly associated with decreased DN risk (odds ratio 0.76 [95% CI 0.61–0.93]). Some evidence of heterogeneity among the included studies was detected, which could be explained by the difference of ethnicity and stage of DN. Subgroup analyses stratified by ethnicity and stage of DN were performed, and results indicated the Pro12Ala polymorphism was associated with the risk of DN in Caucasians but no similar association was observed in Asians. Additionally, we observed that Ala12 was associated with decreased risk of albuminuria. With only a few of subjects were available, we failed to detect statistically significant association between the polymorphism and end-stage renal disease (ESRD).Our results indicated that the Ala12 variant is a significantly protective factor for DN. Future research should focus on the effect of Pro12Ala polymorphism on ESRD and gathering data of Africans.