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Several studies have linked the association between lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and the presence of insulin resistance (IR) due to an underlined metabolic syndrome (MetS).This study aims to determine the relationship between IR, sexual function, and LUTS and to demonstrate the ability of IR in predicting ED and severe LUTS.Between January 2008 to January 2013, 544 consecutive patients with benign prostatic hyperplasia-related LUTS were enrolled. LUTS and sexual function of the patients were evaluated by the International Index of Erectile Function (IIEF) and the International Prostate Symptom Score (IPSS). MetS was defined by the International Diabetes Federation. IR was defined as a homeostasis model assessment (HOMA) index of 3 or greater.Uni- and multivariate logistic regression analysis was performed to assess significant predictors of severe LUTS (IPSS ≥20) and ED (IIEF-Erectile Function [IIEF-EF] <26), including MetS component, prostate volume, prostate-specific antigen, total testosterone, and HOMA index.IR patients resulted in higher values of IPSS (19.0 vs. 15.0; P < 0.01), IPSS-storage (6.0 vs. 5.0; P < 0.01), IPSS-voiding (12.0 vs. 9.0; P < 0.01), total prostate volume (54.8 vs. 36.5; P < 0.01), and lower values of IIEF-EF (17.0 vs. 20.0; P < 0.01), IIEF-Intercourse Satisfaction (3.0 vs. 10.0; P < 0.01), IIEF-Orgasmic Function (8.0 vs. 9.0; P < 0.01), IIEF-Overall Satisfaction (6.0 vs. 8.0; P < 0.01), and total testosterone (3.83 vs. 4.44; P < 0.01). IR was demonstrated to be a strong predictor of ED (IIEF-EF <26) (odds ratio [OR] = 6.20, P < 0.01) after adjusting for confounding factors. Finally, IR was also an independent predictor of severe LUTS (IPSS ≥20) (OR = 2.0, P < 0.01) after adjusting for confounding factors.IR patients are at high risk of having severe LUTS and contemporary sexual dysfunctions. We strongly suggest to prevent LUTS and ED by reducing insulin resistance. Russo GI, Cimino S, Fragalà E, Privitera S, La Vignera S, Condorelli R, Calogero AE, Castelli T, Favilla V, and Morgia G. Insulin resistance is an independent predictor of severe lower urinary tract symptoms and of erectile dysfunction: Results from a cross-sectional study. J Sex Med 2014;11:2074–2082.