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Abstract: Background: Only a small proportion of subjects referring to hospitals for hepatitis C virus (HCV) positivity receives antiviral therapy. Aim: To evaluate the rate of antiviral treatment and the causes for no treatment in HCV-RNA positive subjects seen in hospital settings. Patients and methods: A prospective study enrolling over a 6-month period (February–July 2009) all consecutive anti-HCV positive subjects initially referred (naïve patients) to 12 liver units in Southern Italy for HCV treatment. Results: Out of 608 subjects evaluated, 74 (12.2%) had no detectable HCV-RNA in the serum and thus were excluded. Of the remaining 534 HCV-RNA positive subjects, 357 (66.9%) were not treated for the following reasons: 49.9% were older than 65 years of age (75% of them >70 years), 14.3% had normal liver enzymes, 13.2% had compensated/decompensated cirrhosis, 10.4% refused treatment, 9.8% had ongoing substance or alcohol abuse. Multivariate analysis showed that females (O.R. 2.27; C.I. 95% 1.05–4.90) and subjects with low educational level (O.R. 4.38; C.I. 95% 1.27–15.11) were more likely to decline therapy. Conclusions: The majority of patients with HCV infection does not receive antiviral treatment. The effectiveness of the current standard therapy for HCV infection is low despite its good efficacy. [ABSTRACT FROM AUTHOR]