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Background: RNA-dependant protein kinase R (PKR) is a primary mediator in the defence mechanism of interferon against viral replication and pathogenesis during Hepatitis C virus (HCV) infection. In the present study, we have examined the role of Single Nucleotide Polymorphisms (SNPs) in the promoter region of PKR and the serum level of the same protein on the outcome of HCV-infected Egyptian patients., Patients and Methods: Genomic DNA was extracted from a total of 135 subjects, including 15 healthy controls, 40 HCV spontaneous resolvers (SRs), and 80 patients with chronic HCV infection. PKR genotyping was assessed using DNA sequencing. Finally, serum levels of PKR, TNF-α, INF-γ, and IL-10 were measured using ELISA technique., Results: Serum levels of PKR, TNF-α, and INF-γ showed a significant increase in SRs as compared to chronic HCV patients. On the other hand, serum levels of IL-10 were significantly higher in chronic HCV patients compared to SRs. The present study demonstrated two novel SNPs in the PKR promoter region: at -226 C/T and -141 C/G. The PKR SNP at -226 C < T correlated with HCV-infected patients (genotype 4a) outcome among Egyptians. Our data showed the unique presence of the TT genotype in SRs group (three patients: 7.5%) in PKR -226 C/T. Interestingly, subjects with the TT genotype were more likely to clear their HCV infection than those with the CC genotype., Conclusion: Our work provides more detail about PKR gene polymorphism in HCV genotype 4a as a new clinical tool for anticipating HCV-4a infection outcome.