Background/Aims: Hepatitis C (HCV) infected patients have significant health-related quality of life (HRQL) impairment which worsens during anti-viral therapy. Our aim was to examine the association of HRQL with treatment-induced depression and anemia. Methods: Two hundred and seventy-one HCV patients who received pegylated interferon alfa 2b and ribavirin were included. Data on HRQL, depressive symptoms, laboratory values and socio-demographic characteristics were collected. Results: Mean age was 47.1± 6.5, 69% were male, and 73% were White. HCV patients’ HRQL declined during anti-viral therapy but returned to or exceeded baseline levels within 24 weeks of completion. Anemia and depression were both associated with HRQL impairment. The effects of depression on HRQL were strong; once depression scores were included other factors were no longer significant. Patients’ depressive symptoms tended to increase during the initial half of treatment regimen. Those with higher body mass index (BMI), cirrhosis, and women reported more HRQL impairments. HRQL scales were generally not associated with alcohol abuse, age, race, ALT and HCV RNA levels. Conclusions: Antiviral therapy for HCV is associated with diminished HRQL. Although anemia and depression were associated with this impairment, depression was the most consistent predictor. Future studies are needed to see whether proactive management of these side effects can improve patients’ HRQL and the efficacy of antiviral therapy for hepatitis C. Background / Aims: Hepatitis C (HCV) infected patients have significant health-related quality of life (HRQL) impairment which worsens during anti-viral therapy. Our aim was to examine the association of HRQL with treatment-induced depression and anemia. Methods: Data on HRQL, depressive symptoms, laboratory values ​​and socio-demographic characteristics were collected. Results: Mean age was 47.1 ± 6.5, 69% were male, and 73% were White. HCV patients’ HRQL declined during anti-viral therapy but returned to or exceeded baseline levels within 24 weeks of completion. Anemia and depression were both associated with HRQL impairment. The effects of depression on HRQL were strong; scores were included other factors were no longer significant. Patients’ depressive symptoms tended to increase during the initial half of treatment regimen. Those with higher body mass index ( BMI), cirrhosis, and women reported more HRQL impairments. HRQL scales were generally not associated with alcohol abuse, age, race, ALT and HCV RNA levels. Conclusions: Antiviral therapy for HCV is associated with diminished HRQL. with this impairment, depression was the most consistent predictor. Future studies are needed to see whether proactive management of these side effects can improve patients’ HRQL and the efficacy of antiviral therapy for hepatitis C