Background: Toll-like receptors play important roles in innate and adaptive immunity and polymorphisms within TLR-4 as Asp299Gly are reported to be associated with certain digestive cancers e.g. colorectal carcinoma. Aim: Investigate the association between Asp299Gly polymorphism and the risk of colorectal cancer development and progression. Setting: National cancer institute, Tanta City, Gharbia Governorate, Egypt and/Tanta University Hospitals, General surgery Dept. Study design: A case control study. Patients and Methods: the study included 40 newly diagnosed patients with colorectal cancer recruited from patients attending National Cancer Institute and 40 apparently healthy individuals from relatives/visitors of patients matched in age and sex. For each of patients and control group genotyping of TLR-4 gene by PCR/RFLP was done and confirmed by direct sequencing. Results: TLR-4 Asp299Gly homozygous and heterozygous genotypes were detected in 50% and 30% of the patients respectively. The difference was statistically significant; TLR-4 Asp299Gly homozygous and heterozygous genotypes were significantly associated with advanced stages. Conclusion: TLR-4 Asp299Gly polymorphism is associated with increased susceptibility for CRC development and progression.