Background and Aim of work: HCV is presently considered one of the major health problem worldwide. This study aimed to determine the relationship between Osteopontin gene polymorphism & its protein level and the efficacy of interferon-based therapies in HCV patients.Subjects and Methods: The study included 80 patients with chronic hepatitis C received PEG-IFN alpha-2b plus ribavirin for 24 weeks. and 20 healthy subjects serving as control. physical and clinical examination and 10 ml of blood were collected from each subject. The following was done; Liver function tests, hepatitis markers, HCV quantitation by real time PCR, DNA extraction from whole blood, agarose gel electrophoresis followed by sequence analysis and quantitation of protein level of osteopontin by ELISA.Results: SNP in the promotor region of the osteopontin gene (OPN) at nucleotide (nt) -155 show significant difference between responders and non responders by univariate logistic regression analysis (p=.011) but not by multivariate logistic regression analysis (p=.204).Also, there was a significant difference between responders and non responders as regards plasma osteopontin protein level by both univariate and multivariate logistic regression analysis (p=.000) and (p=.015) respectively.Conclusion: SNP in the promotor region of the osteopontin gene (OPN) at nucleotide (nt) -155 and serum OPN protein level are predictors of response to combination therapy of HCV.