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Abstract: Recent studies reported a close correlation between polymorphisms in the Interleukin (IL)28B gene and rates of resolution of hepatitis C virus infection occurring spontaneously or induced by treatment. The diagnostic utility of IL28B genotype, however, is not understood completely. For rapid data collection on the natural history of HCV infection in patients with different IL28B genotype, simple, sensitive and rapid methods suitable for non-invasive and archival clinical samples are needed urgently. A real-time polymerase chain reaction (PCR) method for IL28B typing (rs12979860) was developed using very small DNA quantities extracted from different biological specimens. Consistent IL28B genotyping of at least two DNA samples obtained from different sources such as whole blood, buccal swab, serum, and formalin fixed paraffin-embedded liver tissue was obtained from 58 patients with liver disease of mixed etiology. IL28B genotype prevalence in 170 patients with liver disease in this region of Italy was consistent with data reported in Caucasian populations. Differential distribution of genotypes was observed according to response to treatment in 68 patients infected with HCV, with higher prevalence of CC genotype in responders (50%) compared to non-responders (17.85%; p =0.015). These results indicate that the possibility of reliable IL28B genotyping using different DNA sources may represent a useful tool for both clinical research and characterization of patients with hepatitis C. [Copyright &y& Elsevier]