The aim of the study was to evaluate the association between the gene polymorphisms in interleukin-10 (IL-10) and interferon gamma (IFN-gamma) genes with susceptibility and severity of hepatitis C virus (HCV) infection among Egyptian patients. Interleukin-10 -592 A/C, -1082 G/A and IFN-gamma + 874 T/A genotypes were determined in 100 chronic HCV patients and 50 healthy controls using restriction fragment length polymorphism (RFLP) and the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) respectively. IL-10 -592 A/C polymorphism genotyping revealed that the frequency of CC genotype was significantly higher in chronic HCV patients than in controls (58% versus 30%, P < 0.05). Regarding IL-10 -1082 G/A polymorphism genotyping, a higher frequency of GG genotype was found in chronic HCV patients compared to controls (31% versus 10%, P < 0.05). IFN-gamma + 874 T/A genotyping showed that TT genotype was significantly higher in chronic HCV participants than controls (31% versus 18%, P< 0.05), while a higher frequency of T allele was found in cirrhotic patients compared to noncirrhotic patients (P< 0.05). Our observations suggested that IL-10 -592 A/C, -1082 G/A, and IFN-gamma + 874 T/A polymorphisms had a strong association with susceptibility to HCV infection. However, no significant association was observed between the cytokines (IL-10 and IFN-gamma) genotypes profile and HCV-liver cirrhosis risk in the studied population, except for the high frequency of IFN-gamma + 874 T allele in cirrhotic patients.