Background and Aim: Chronic infection with hepatitis C virus (HCV)is a huge problem both globally and at the level of the individual patient.The natural outcome and response to treatment in hepatitis C virus infectionvaries between individuals. We aimed to determine the incidence of vitaminD deficiency in patients with chronic hepatitis C. In addition, we evaluatedassociations of vitamin D (Vit D) serum levels as well as polymorphismwithin gene encoding 1α-hydroxylase with the virologic response ofinterferon-Alfa based treatment in patients chronically infected with HCV inEgypt.Subject and Methods: Blood samples were taken from 103 patients whoare suffering from chronic hepatitis C disease and prepared for interferontreatment. Also 30 blood samples from controls were taken.The following were done: history taking, general examination, liverfunction tests, hepatitis markers, HCV quantitation by real time PCR, DNAextraction from whole blood, PCR for gene amplification, agarose gelelectrophoresis and quantitation of serum level of vitamin D by ELISA.Results: there is significant differences in the Prevalence of vitamin Ddeficiency between responders and non responders to interferon therapy ofchronic hepatitis C patients (P=0.003). Stepwise multivariate logisticregression showed that Vit D (P = 0.002) and CYP27B1-1260 (P = 0.009)were found to be significant predictors for response to interferon therapy ofhepatitis C patients. There is significant difference in the Vit D level and 1α-hydroxylase promoter polymorphism CYP27B1-1260 in chronic HCV patients (AA, CA, CC) (p=0.000). Also there is significant differencein the Vit D level and 1α- hydroxylase promoter polymorphism CYP27B1-1260 in the healthy control group (AA, CA, CC) (P=0.000).Conclusion: Serum levels of Vitamin D and1α- hydroxylase promoterpolymorphism CYP27B1-1260 are significant predictors for response tointerferon therapy of hepatitis C patients.