Background and rationale It is well established that chronic viral hepatitis (CVH) negatively affects patients' health related quality of life (HRQOL) The aim of the present study was to assess the extent to which fatigue and depressive symptoms are associated with CVH patients' HRQOL Methods Eighty four adult CVH outpatients [45 with hepatitis B virus (HBV) and 39 with hepatitis C virus (HCV) infection] participated in the study The Short Form 36 Health Survey (SF 36), the Beck Depression Inventory II (BDI II) and the Fatigue subscale of the Functional Assessment of Cancer Therapy Anemia Scale (FACT F) were used to assess HRQOL, depression and fatigue, respectively Results All aspects of HRQOL perceived by CVH patients were significantly impaired compared to the general population, as a comparison with Greek population based normative data revealed HBV patients presented similar HRQOL with HCV patients Clinical parameters including infection activity, fibrosis stage or inflammation grade, as well as depressive symptoms and fatigue were found to be significantly associated with HRQOL Multivariate analyses showed that older age (p < 0 001) and higher fatigue scores (p < 0 001) were the variables most closely associated with the physical HRQOL, whereas higher rates on depressive symptoms (p < 0 0005) and fatigue (p < 0 020) scales were the variables most closely associated with the mental HRQOL Conclusions In conclusion, CVH is associated with impaired HRQOL Fatigue and impaired psychological functioning is associated with diminished HRQOL in CHV, independent of the disease etiology Consequently, management of fatigue and depressive symptoms should be considered a priority, in order to improve HRQOL in CVH patients