Background/Aims The erythropoiesis in hepatitis C virus infection is unclear. We aimed to evaluate the erythropoietic components in chronic hepatitis C (CHC) patients. Methods The red blood cell (RBC) components, serum erythropoietin (EPO) levels, and their relationship to clinical characteristics were evaluated between 124 age-matched and sex-matched healthy controls and 248 histology-proven CHC patients. Results Chronic hepatitis C patients had significantly higher serum levels of EPO (1.440.36 log mIU/mL versus 1.03 +/- 0.31 log mIU/mL, P<0.0001) and lower hemoglobin (Hb) concentrations (14.6 +/- 1.4g/dL versus 15.3 +/- 1.2g/dL, P<0.001) as compared with healthy controls. Among the CHC patients, the serum EPO level was negatively associated with the Hb concentration (=-0.227; 95% confidence intervals [CI]: -0.09-0.027; P<0.001) and RBC counts (=-0.204; 95% CI: -0.245-0.061; P=0.001) and was positively correlated with necroinflammatory activity (=0.201; 95% CI: 0.009-0.046; P=0.003) and fibrosis (=0.143; 95% CI: 0.003-0.076; P=0.04) of liver histopathology. For non-cirrhotic CHC patients, the severity of liver necroinflammatory activity was positively correlated with the reticulocyte and serum EPO levels (P=0.001 and 0.008, respectively), and negatively related to the RBC counts (P=0.03). Using stepwise multivariate linear regression analysis, the grade of necroinflammatory activity was positive (=0.214; 95% CI: 0.046-0.209, P=0.002), whereas the Hb concentration was inversely (=-0.205; 95% CI: -0.09-0.018, P=0.004) associated with the serum EPO levels in CHC patients. Conclusions The disease activity in CHC patients had a negative impact on erythropoiesis with compensatory higher but blunted EPO responses.