AIM: To assess serum concentrations of prohepcidin in chronic hepatitis C individuals and evaluate their associations with disease activity and efficacy of pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy. METHODS: Prohepcidin was measured in sera of 53 chronic hepatitis C patients. Concentrations of prohepcidin and other iron metabolism markers were analyzed at 9 time points before, during and after the end of antiviral therapy. RESULTS: In hepatitis C virus (HCV) genotype 1-infected individuals, a gradual decrease of prohepcidin during antiviral therapy was observed in responders (88.8 ± 14.7 ng/mL before therapy vs 60.6 ± 0.3 ng/mL in the 48th wk, P = 0.04). In contrast, no decrease was observed in non-responders. A similar association was observed in HCV genotype 3a individuals, with a statistically significant decline in serum prohepcidin only in the responder group (99.5 ± 5.2 ng/mL at baseline vs 72.7 ± 6.1 ng/mL in the 24th wk, P = 0.01). Moreover, HCVRNA at week 12 of therapy was positively correlated with baseline ( R = 0.63, P < 0.005) and week 12 ( R = 0.60, P = 0.01) serum prohepcidin concentrations in HCV genotype 1 infection. CONCLUSION: Successful PEG-IFN/RBV therapy results in a decline of serum prohepcidin concentration in chronic hepatitis C, which may suggest a direct effect of HCV on iron metabolism at the prohormonal level of hepcidin.