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INTRODUCTION Erectile dysfunction (ED) is usually developed from psychological, neurological, hormonal, and vascular pathologies or a combination of these factors. However, the possible genetic polymorphisms that might underlie this disorder were not thoroughly investigated. OBJECTIVES This review article aimed to assess the possible involvement of gene polymorphisms in men with ED. METHODS A systematic review was conducted until January 2020 based on a search of all relevant articles in many electronic sites such as PubMed, Medline Medical Subject Headings, Science Direct, Scopus, Cochrane Library, EMBASE, CINAHL, and Egyptian Knowledge Bank databases with no language restriction. Keywords used to assess the outcome and estimates for relevant associations were sexual health, genes, erectile dysfunction, polymorphisms, and cavernous tissues. RESULTS Many genetic studies were carried out to inspect the contribution of different encoded genotypes and ED. Overall, 50 studies were reviewed and were classified as per the type of gene polymorphisms. These studies have investigated 10,174 men with ED compared with 6,891 healthy men as controls. 35 studies were case-controlled, 13 cross-sectional cohort studies, one retrospective study, and one genome-wide association study. So far, the most relevant gene polymorphisms linked with men with ED included endothelial nitric oxide synthase (eNOS), angiotensin-converting enzyme (ACE), androgen receptor (AR) CAG repeat, G-protein β3 (GNB3) subunit, methylenetetrahydrofolate reductase (MTHFR), vascular endothelial growth factor (VEGF), TGFB1, proprotein convertase subtilisin/kexin type 9 (PCSK9), ARG1, DRD2, DRD4, DDAH, and HNF4A genes. Both PROGINS and IGFBP-3 polymorphisms were investigated in only one study each but with irrelevant significance. CONCLUSIONS Although several genetic studies exposed the association between different genotypes and men with ED with varied outcomes, such a relationship should not be overlooked. Therefore, more studies should be encouraged to elucidate the exact role, if any, for such association. Mostafa T, Taymour M. Gene Polymorphisms Affecting Erectile Dysfunction. Sex Med 2020;XX:XXX-XXX.