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Goals: To determine the relative impact of chronic hepatitis C (CHC) and comorbid psychiatric illness on the health-related quality of life (HRQoL)., Background: Psychiatric conditions are more common among patients with CHC but their relative influence on HRQoL is not well understood., Study: We identified 864 veterans who had previously completed a veteran-specific HRQoL questionnaire (SF-36V) as part of the 1999 VA Large Health Survey with known HCV antibody (anti-HCV) status before the survey. For 201 anti-HCV(+) and 663 anti-HCV(-) patients, we compared the HRQoL status and the prevalence of 6 major psychiatric diagnoses. We conducted multiple regression analyses to measure the effect of anti-HCV status and psychiatric comorbidity., Results: Compared with the anti-HCV(-) group, anti-HCV(+) veterans were more likely to have alcohol dependence (P<0.001), depression (P=0.01), or posttraumatic stress disorder (PTSD) (P<0.004). The anti-HCV(+) group also reported lower HRQoL on 4 of the 8 SF-36V subscales (P<0.01) and the mental component summary scale (P<0.001). Even after adjusting for demographic variables and comorbid psychiatric illness, anti-HCV(+) patients reported a significantly lower mental component summary score (P<0.01) than did anti-HCV(-) patients. Multiple regression analysis found that depression and PTSD predicted lower HRQoL scores for all 8 HRQoL subscales (P<0.01) and both the physical (P<0.001) and mental component (P<0.03) summary scales independent of anti-HCV status., Conclusions: The HRQoL is significantly impaired in veterans with CHC, particularly the mental health components of HRQoL. In contrast, comorbid depression and PTSD are associated with both lower physical and mental components of HRQol, independent of CHC.