Background: Polymorphisms in the cytokine gene involving IFN gamma (IFN-γ) have been implicated in many infections including HCV. The aim of this study is to evaluate the association between IFN-γ polymorphism in three regions, (+2109A/G, +874A/T, -183G/T) and either chronicity or spontaneous viral clearance (SCV) in HCV infected patients. Materials and Methods: The study included 200 HCV-infected patients divided into Group I of 100 patients with spontaneous virus clearance (SVC) and Group II of 100 patients with persistent chronic hepatitis C infection (PI) who did not receive any therapy. These patients were subjected to history taking, full clinical examination and laboratory investigations included analysis of IFN-γ gene polymorphisms. Results: At locus +2109 of the IFN-γ gene, patients with A/A genotype had a significantly higher rate of spontaneous hepatitis C clearance while the G/G genotype was more prone to persistent infection. No statistically significant difference was found between both groups regarding loci +874 and -183 of the IFN-γ gene, but column proportion comparison using Bonferroni method at locus +874 revealed a higher proportion for T/A genotype in SVC group. Both haplotypes AAT and TGT were more susceptible to chronic HCV infection, as were heterozygote T/A at locus +874 and G/G genotype at locus +2109s. A/G and A/A genotypes at locus +2109, TLC at cut off value ≤7.15, and AST at cut off value ≤27.5 were considered independent predictors for development of SVC. Conclusions: Polymorphisms in the IFN-γ gene may play role in sequelae following HCV infection, possibly determining whether the virus will be cleared spontaneously or not.