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Retinol-binding protein 4 (RBP4) is a recently identified adipokine that is elevated in the blood in several insulin-resistant states. We investigated the association between plasma RBP4 and histological and biochemical characteristics of chronic hepatitis C (CHC), as well as changes in RBP4 levels following interferon therapy. Eighty-one patients with CHC infected with genotype 1 received treatment with peginterferon plus ribavirin. Histological data were available for 41 out of 81 patients before treatment, and the degree of fibrosis, inflammation and steatosis was assessed. Plasma levels of RBP4 were determined in serial samples (before, at the end of treatment, and at 6 months post-treatment). RBP4 levels were lower in CHC patients than in control subjects (34.6 ± 12.3 μg/mL vs 46.2 ± 10.5 μg/mL; P ≤ 0.001). Higher RBP4 levels were linked to lower alanine aminotransferase (ALT) (P < 0.01), higher cholinesterase (P < 0.01), hyperlipidaemia (P < 0.01), hyperglycaemia (P < 0.05), and higher platelet (P < 0.01) count in CHC patients. Plasma RBP4 levels tended to decrease concomitantly with the grade of histological fibrosis, activity, and steatosis. RBP4 levels at baseline were not a predictor of the response to antiviral therapy in CHC patients. After peginterferon plus ribavirin therapy, only patients who had achieved clearance of hepatitis C virus had higher post-treatment RBP4 levels. This study suggests that an association between RBP4 levels and abnormal metabolic features, and that liver function may determine RBP4 levels in CHC patents. This is further supported by the observation that RBP4 levels increased significantly after treatment only in sustained virological response (SVR) patients and reached levels comparable to those of healthy subjects.