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Fat mass and obesity-associated (FTO) is considered the first locus associated with adiposity, a concerning health problem worldwide. Many studies have evaluated the relationship between the FTO variants and obesity susceptibility. While the strong association of FTO rs1421085 with the risk of obesity across populations was reported in different studies, some researchers found a lack of association of this variant with adiposity. This systematic review and meta-analysis aimed to assess the association between obesity and rs1421085 polymorphism.We systematically searched PubMed, Scopus, and Google Scholar up to June 2022 to find pertinent studies. To further assess this issue, we surveyed the probable association of rs1421085 with obesity development among Iranian adults using the logistic regression analysis, and the obtained results were used for doing meta-analysis. After selection, nine eligible studies were included in the meta-analysis through the random- and fixed-effect models to determine the combined odds ratios (OR) and 95% confidence intervals (CI).According to our meta-analysis conducted on 5169 obese and 7772 non-obese individuals using different genetic models, including recessive, dominant, over-dominant, and additive, rs1421085 could positively increase the risk of obesity under all tested genetic models. Also, we detected a high to moderate level of heterogeneity among different studies under various genetic models.This meta-analysis further verified the positive association of FTO rs1421085 with the risk of developing obesity.This study is registered as PROSPERO CRD42021220092.Level I, systematic reviews and meta-analyses.