Objective: Patients with chronic hepatitis C (CHC) have a poorer quality of life than those with other chronic liver diseases. However, some of the factors that determine health-related quality of life (HRQOL) in these patients, such as the degree of liver fibrosis, are still controversial. Therefore, the aim of the present study was to investigate the impact of CHC on HRQOL by conducting clinical, psychiatric, and sociodemographic evaluations. Methods: One hundred and twenty-four consecutive patients attending a referral center for hepatitis were evaluated using the Mini-International Neuropsychiatry Interview, the Hamilton Depression Rating Scale, the Hospital Anxiety and Depression Scale, and the Medical Outcomes Study 36-Item Short-Form Health Survey. Multiple linear regression analyses were used to quantify independent associations between HRQOL and the clinical, psychiatric, and sociodemographic variables of interest. Results: Reduced HRQOL was independently associated with major depressive disorder (MDD) and with elevated levels of alanine aminotransferase, but was not associated with hepatic cirrhosis. Conclusions: MDD rather than the grade of liver fibrosis was strongly associated with HRQOL impairment in patients with CHC. These findings highlight that, in patients with CHC, the psychological effects of the disease deserve more attention and the implementation of integrated medical, psychiatric, and psychological care may be helpful.