Egypt has the highest prevalence of hepatitis C virus (HCV) in the world. It has been suggested that not only the virus but also the interaction between the virus and the host immune system is important in determining the course of the infection and the response to interferon (IFN)-based therapy. While the adaptive immune system plays a critical role in HCV infection, the innate immune system has only been recognized recently. Toll-like receptors (TLRs) form the cornerstone of the innate immune response. Interleukin-10 (IL-10) is one of the upstream regulators of TLR4. A possible interplay between TLR4 and IL-10 has been suggested. The present study aimed to investigate the role of single-nucleotide polymorphisms (SNPs) in TLR4 and IL-10-1082 and the expression levels of these proteins in predicting the response to treatment in chronic HCV patients. A total of 83 chronic HCV-infected Egyptian patients treated with peg-IFN-α2b-ribavirin combination therapy and 40 healthy subjects were included in this study. SNPs in the TLR4 rs2149356 and IL-10-1082 genes and their serum levels were assessed. Within the responders group, T/T and A/A genotypes were the significantly most frequent genotypes of TLR4 and IL-10-1082, respectively. Moreover, a higher frequency of T/T and A/A was found to be associated with lower serum TLR4 and IL-10 levels in our responder patients. In addition, subjects with the T/T genotype in the healthy control group had a lower serum TLR4 level than those with other genotypes. We conclude that the SNPs TLR4 rs2149356-T/T and IL-10-1082-A/A may be important predictors for HCV therapy.