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Background: Colorectal cancer (CRC) ranks third in cancer incidence globally and is the second leading cause of cancer-related mortality. The nucleoside diphosphate kinase 1 (NME1)and netrin 1 receptor (DCC)genes have been associated with resistance against tumorigenesis and tumor metastasis. This study investigates the potential association between NME1(rs34214448 G > T and rs2302254 C > T) and DCC(rs2229080 G > C and rs714 A > G) variants and susceptibility to colorectal cancer development. Methods: Samples from 232 colorectal cancer patients and 232 healthy blood donors underwent analysis. Variants were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) methodology. Associations were assessed using odds ratios (OR), and the pvalues were adjusted with Bonferroni test. Results: Individuals carrying the G/T and T/T genotypes for the NME1rs34214448 variant exhibited a higher susceptibility for develop colorectal cancer (OR = 2.68, 95% CI: 1.76–4.09, P= 0.001 and OR = 2.47, 95% CI: 1.37–4.47, P= 0.001, respectively). These genotypes showed significant associations in patients over 50 years (OR = 2.87, 95% CI: 1.81–4.54, P= 0.001 and OR = 2.99, 95% CI: 1.54–5.79, P= 0.001 respectively) and with early Tumor-Nodule-Metastasis (TNM) stage (P= 0.001), and tumor location in the rectum (P= 0.001). Furthermore, the DCCrs2229080 variant revealed that carriers of the G/C genotype had an increased risk for develop colorectal cancer (OR = 2.00, 95% CI: 1.28–3.11, P= 0.002) and were associated with age over 50 years, sex, and advanced TNM stages (P= 0.001). Conclusions: These findings suggest that the NME1rs34214448 and DCCrs2229080 variants play a significant role in colorectal cancer development.