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BACKGROUND The causal relationship between obesity-related anthropometric indicators/body composition and erectile dysfunction (ED) has not been established in previous observational studies. METHOD We screened single nucleotide polymorphisms significantly associated with exposure from genome-wide association studies (GWAS) as instrumental variables (IVs) (P < 5.0 × 10-8 ). The summary statistics for ED were collected from a GWAS with a sample size of 223,805. Exposure and outcome populations included are of European ancestry. We used univariate and multivariate Mendelian randomization (MR) (i) to investigate the causal relationship between genetically predicted obesity-related anthropometric indicators/body composition and ED (ii) to examine the mediating role of coronary artery disease (CAD). MR analysis was conducted using an inverse variance weighted method. A series of sensitivity analyses validated the results of the MR analysis. Causal estimates are expressed as odds ratios (OR) with 95% confidence intervals (CI). RESULTS Obesity-related anthropometric indicators/body composition were associated with an increased risk of ED in univariate MR analyses. For the 1-SD increase in BMI, the OR was 1.841 (95% CI: 1.049-1.355, P = 0.006). For the 1-SD increase in waist circumference and hip circumference, the ORs were 1.275 (95% CI: 1.101-1.478, P = 0.001) and 1.156 (95% CI: 1.015-1.317, P = 0.009), respectively. The OR for the 1-SD increase in whole body fat mass was 1.221 (95% CI: 1.047-1.388, P = 0.002). For the 1-SD increase in leg fat percentage (left & right), the ORs were 1.256 (95% CI: 1.006-1.567, P = 0.044) and 1.285 (95% CI: 1.027-1.608, P = 0.028), respectively. For the 1-SD increase in leg fat mass (left & right), the ORs were 1.308 (95% CI: 1.108-1.544, P = 0.001) and 1.290 (95% CI: 1.091-1.524, P = 0.003), respectively. For the 1-SD increase in arm fat mass (left & right), the ORs were 1.269 (95% CI: 1.113-1.447, P < 0.001) and 1.254, respectively. Multivariate MR analysis showed that after adjusting for CAD, some genetic predispositions to obesity-related anthropometric indicators and body composition were still associated with an increased risk of ED. Significant associations were found for waist circumference-ED (OR: 1.218, 95% CI: 1.036-1.432), leg fat percentage (left)-ED (OR: 1.245, 95% CI: 1.035-1.497), leg fat mass (left)-ED (OR: 1.264, 95% CI: 1.051-1.521), arm fat mass (right)-ED (OR: 1.186, 95% CI: 1.024-1.373), and arm fat mass (left)-ED (OR: 1.17, 95% CI: 1.018-1.360). Meanwhile, CAD mediated the effects of fat on ED, and the proportion of CAD-mediated cases ranged from 10% to 22%. CONCLUSION There is a potential causal relationship between obesity-related anthropometric indicators/body composition and ED. Higher waist circumference, leg fat percentage, and arm fat mass may increase the risk of ED, and CAD partly mediates this overall effect. Understanding the causal relationship between obesity and ED and the mediating role of CAD may provide more information for ED intervention and prevention strategies. This article is protected by copyright. All rights reserved.