Immune response variations could define successful resistance to Hepatitis C Virus (HCV) infection. Toll-like receptors (TLR)-3 are innate detectors of dsRNA viruses while bacterial and viral unmethylated CpG motifs are recognized by TLR9. We previously reported that TLR3.rs3775290 “CC” genotype was associated with HCV chronicity, while TLR9 gene played no major role in this infection. This study identified the role of TLR3.rs3775290 (c.1377C/T), TLR9.rs5743836 (-1237T→C) and TLR9.rs352140 (G2848A) gene polymorphisms in predicting the outcome of HCV-specific cell-mediated immunity (CMI) among Egyptian healthcare workers (HCWs) and patients. We enrolled 546 subjects (409 HCWs and 137 patients) divided into four groups. Group1: 265 seronegative, aviraemic subjects; group2: 25 seronegative, viraemic subjects; group3: 87 subjects with spontaneously resolved HCV infection; and group4: 169 chronic HCV HCWs and patients. All subjects were genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis for the TLR3.rs3775290, TLR9.rs5743836 and TLR9.rs352140 SNPs. We, also, quantified HCV-specific CMI in 265 HCWs distributed among the four groups using an interferon gamma (IFN-γ) enzyme-linked immunospot (ELISpot) assay in response to nine HCV genotype 4a overlapping 15mer peptide pools covering the whole viral genome. No statistically significant difference was found between CMI responding subjects with different HCV states and TLR3.rs3775290 genotype or TLR9.rs352140. However, there was a significant relationship between the outcome of the HCV-specific CMI and the TLR9.rs5743836 genotype among the responding subjects (p=0.005) and the chronic HCV patients (p=0.044). In conclusion, TLR9.rs5743836 SNP; but not TLR3.rs3775290 or TLR9.rs352140 genotypes; could predict the outcome of HCV-specific CMI responses among genotype-4-infected Egyptians.