Erectile dysfunction has been described as a sentinel marker of co-existing and undetected cardiovascular disease. Beside cardiovascular diseases, a correlation between erectile dysfunction and other major comorbidities has been also reported. The study was aimed to analyze the association between sexual functioning and overall men's health in sexually active, Caucasian-European men with new-onset sexual dysfunction. Data from the last 881 consecutive patients seeking first medical help for sexual dysfunction were cross-sectionally analyzed. The International Classification of Diseases, 9th revision, Clinical Modification was used to classify health-significant comorbidities, which were scored with the Charlson Comorbidity Index (CCI). A modified CCI score from which all potential cardiovascular risk factors (CCI-CV) were subtracted was then calculated for every patient. Patients were requested to complete the International Index of Erectile Function (IIEF). The main outcome of the study was the association between the IIEF domain scores and CCI, which scored health-significant comorbidities even irrespective of cardiovascular risk factors (CCI-CV). The final sample included 757 patients (85.9%) (Median age: 48 years; IQ range: 37-59). Overall, erectile dysfunction was found in 540 (71.4%) patients. Of these, 164 (21.6%) had a CCI ≥ 1 and 138 (18.2%) had a CCI-CV ≥ 1, respectively. At the analysis of variance, IIEF-Erectile Function (EF) scores significantly decreased as a function of incremental CCI and CCI-CV scores (all p <0.01). At multivariable logistic regression analysis, both IIEF-EF and IIEF-total score achieved independent predictor status for either CCI ≥ 1 or CCI-CV ≥ 1, after accounting for potential confounders (p <0.01). We report novel findings of a significant association between erectile dysfunction severity and overall men's health, even irrespective of cardiovascular risk factors. Thereof, erectile dysfunction severity could serve as a proxy for general men's health, thus encouraging physicians to comprehensively assess patients complaining of sexual dysfunction in the real-life everyday clinical practice. © 2016 American Society of Andrology and European Academy of Andrology.