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Although sexual dysfunction has been reported in patients with hepatitis C virus (HCV) infection, little is known about this association. The aims of this study were to determine the prevalence of sexual dysfunction among men with chronic HCV infection and to evaluate the impact of sexual dysfunction on health-related quality of life (HRQOL).We prospectively enrolled 112 HCV positive men and 239 HCV negative controls, and all patients completed validated questionnaires to assess sexual function (Brief Male Sexual Function Inventory [BMSFI]), depression (Beck Depression Inventory), and HRQOL (Medical Outcomes Study Short Form-36). The BMSFI assessed sexual drive, erection, ejaculation, sexual problem assessment, and overall sexual satisfaction.HCV positive men had significantly more sexual dysfunction than control subjects across all five domains of the BMFSI. In addition, HCV-infected men were significantly more likely than controls to not be sexually satisfied (53.6% vs 28.9%, p < 0.001) and this remained statistically significant after adjusting for age, race, and other potential confounding variables (OR = 3.36; 95% CI, 1.59–7.13). In the 241 individuals without depression, HCV positive men were significantly more likely to not be sexually satisfied as compared with control subjects (47.5% vs 11.0%, p < 0.001). HCV-infected men who were not sexually satisfied scored significantly worse in six of eight domains of HRQOL as compared with HCV-infected men who were sexually satisfied.Sexual dysfunction is highly prevalent in men with chronic HCV infection, is independent of depression, and is associated with a marked reduction in HRQOL.