Hepatitis C virus (HCV) is a major cause of chronic liver disease, with about 170 million people infected worldwide. The standard regimen for treatment of HCV consists of a combination of pegylated interferon with ribavirin. Failure of interferon-α treatment in patients with chronic HCV infection remains a challenging obstacle. Both viral and host environmental factors have been implicated in reducing responsiveness to IFN-α therapy. Host genetic diversity is also believed to contribute to the different clinical outcomes in HCV infection. The objective of the study was to investigate the association of both IL-10 (-819 and -592) and MxA (-88 and -123) single-nucleotide polymorphisms (SNPs) of the promoter regions, with response to interferon (IFN) therapy in Egyptian patients infected with HCV genotype 4. Polymorphisms of both genes in 85 HCV patients and 100 controls were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of SNP was compared between sustained responders (n = 52) and non-responders (n = 33), as determined by biochemical and virological response to IFN and ribavirin combined therapy. The frequency of the -819T/T and the -592A/A genotypes of IL-10 was significantly higher among responders compared to non-responders (51.92 vs 39.4 %, P = 0.03; 51.92 vs 42.42 %;P = 0.046 respectively). The G/G genotype at position -88 of the MxA gene was significantly lower in responders than in non-responders (25 vs 75.76 %, P = 0.046), whereas heterozygotes (G/T) were more likely responders (65.38 vs 18.18 %, P = 0). The -123C/A genotype was significantly associated with responders (48.08 vs 30.30 %, P = 0.014). Findings suggest that homozygosity for both -819T/T and -592A/A polymorphisms of IL-10 gene and that heterozygosity for both -88G/T and -123C/A polymorphisms of the MxA gene are important host factors that influence the response to IFN therapy in patients with chronic HCV infection.