Objective: Tumour necrosis factor (TNF)-alpha, a prototype proinflammatory cytokine, has been implicated as an important pathogenic mediator in a variety of liver conditions. Some genetic polymorphisms in the human TNF-alpha promoter region, such as the G-A transitions -308 and – 238, have been shown to influence TNF-alpha expression in chronic hepatitis C virus infection. Aim of the work: The present study was to investigate the influence that the – 308and – 238 TNF- alpha promoter polymorphisms have on the response to interferon and ribavirin therapy in chronic hepatitis C virus infection. Patients and methods: One hundred forty patients with chronic hepatitis C virus infection, their age ranges between (20-56) years, selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, during interferon and ribavirin therapy and thirty five healthy individuals were included to serve as controls, the patients and controls were divided into two groups the first group forty patients and fifteen controls for the detection of TNF-alpha -308, -238 genotypes polymorphisms, the second group were one hundred patients and twenty healthy controls for the detection of  serum levels of   TNF-α. All the patients and controls were subjected to the following history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigation, CBCs and serological assay, genotyping of 308, 238 TNF-alpha promoter polymorphism and serum levels of  TNF-α. Results: There was no statistically significant difference between chronic HCV patients   and healthy controls as regarding TNF-alpha -238 different alleles. The frequencies of TNF-alpha gene polymorphism with A/G and G/G mutation at – 308 were significantly higher in chronic HCV patients than those in the controls. The serum level of TNF-alpha was markedly higher in the chronic HCV patients than in the healthy controls. There were significant association between TNF- alpha gene polymorphism in the – 308 A/G, G/G alleles and increased serum TNF- alpha in CHCV infection. Conclusion: The results indicate that the TNF-alpha gene polymorphism at position -308 is associated with susceptibility of chronic HCV infection. Recommendations: Our major concern was to improve the response to treatment in patients with chronic  HCV infection, whether the disadvantage of having the TNF-alpha -308 allele became more apparent after interferon and ribavirin therapy is unclear and needs further study that detecting the polymorphism of the -308 TNF-alpha allele before administering interferon therapy may be valuable for predicting the treatment response, especially in difficult- to treat patients.