Prevalence of Hepatitis C virus (HCV) in Egypt is 22% as reported by World Health Organization (WHO) 2012. Interferon (IFN)-based treatments are currently the main therapeutic option. However, depending upon variations in their human leukocyte antigen (HLA), some patients do not respond well to IFN therapy. The current study evaluated some HLA class II alleles among 200 HCV positive individuals from Alexandria, Egypt, who were receiving standard IFN therapy. In this study, 30 patients (33.3 %) showed a sustained virological response (SVR) to IFN therapy, whereas 30 (33.3 %) did not and 30 (33.3%) cleared the virus spontaneously. 30 unrelated healthy volunteers served as controls. DNA was extracted by spin column method from lysed blood of all enrollees for HLA-DRB1 and HLA-DQB1 allele typing by sequence specific oligonucleotide probe (SSOP), whilst plasma was used for HCV quantitation by real time polymerase chain reaction (RT-PCR) and genotyping by line probe assay INNO LiPA (Innogenetics). HLA-DRB1*03 individually (p=0.025) or in combination HLA-DRB1*04 (p=0.035) revealed to be significant protective alleles against HCV infection. In patients on IFN therapy, HLA-DRB1*11 was significantly associated with viral clearance. In contrast, HLA-DRB1*07 (p=0.005) was associated with viral persistence. We can conclude that certain HLA class II alleles could predict response to IFN therapy as early as possible before starting treatment of chronic HCV cases and can be used as successful guide to clinicians in deciding the therapeutic regimen for Egyptian patients infected with HCV genotype 4.