OBJECTIVES: Chronic hepatitis C (CHC) is a common condition and diminishes health related quality of life (HRQOL).  Depression is the most prevalent psychiatric condition in CHC patients and may further impair HRQOL.  We sought to identify the relative contribution of modifiable patient factors associated with poor HRQOL in depressed CHC patients. These data can provide a blueprint of how best to target interventions in order to improve the HRQOL of this vulnerable group of patients. METHODS: Telephone-based structured interviews were conducted on depressed CHC patients (PHQ9 sore ≥10) seeking care at four VA medical centers during 2012-2013. Depression severity was measured using the Symptom Checklist 20 (SCL-20), generalized anxiety disorder (GAD) using the Mini-International Neuropsychiatric Interview (MINI), and HRQOL with the Short Form-12 (SF12).  Medical charts were reviewed for baseline severity of liver disease (presence of cirrhosis).  Bivariate and multivariable linear regression models were used to identify predictors of standardized physical (PCS) and mental (MCS) component HRQOL scores. RESULTS: Complete HRQOL data were available for 160 patients (mean age 58.9+5.2 yrs.); 97.5% male; 56% African American; and 41% married.  The mean baseline SF12 PCS and MCS were 35.2±12.3 and 35.3±10.1, respectively.  Individuals with more severe depression and GAD were more likely to report poor PCS (p<0.05).  Similarly, with higher depression and GAD scores, receiving care for mental health, as well as current antidepressant use  was associated with poor MCS (p<0.05).  There was no association between stage of liver disease and HRQOL (p>0.05).  After adjusting for demographics, clinical characteristics, and study site, higher depression was associated with both poor PCS and MCS (p<0.05).   CONCLUSIONS:  HRQOL decrement in CHC patients with depression is primarily related to the severity of psychosocial disorders. These data support focusing efforts on co-existing mental health to improve patients HRQOL.