During the transformation process single nucleotide polymorphisms (SNPs) of key genes, such as p53 Arg72Pro or EGF A61G, may mediate various cellular processes. These variants may be associated with colorectal cancer risk (CRC), but conflicting findings have been reported. The purpose of this study was to determine the association of the SNPs in 5′ UTR of EGF A61G and p53 Arg72Pro and CRC in the Slovak population. The present case-control study was carried out in 173 confirmed CRC patients and 303 healthy subjects. Genotyping was performed by PCR-RFLP methods. Significant association was observed between age and CRC risk (p=0.001). Lower CRC risk was seen in younger patients carrying genotype p53 Arg72Pro (0.14; 95% CI 0.02–0.99, p=0.049). Gender-stratified analysis showed a significant inverse association of the polymorphism EGF G61G with CRC risk (0.48; 95% CI 0.2–0.9, p=0.04) only in male patients. Tumour site genotype distribution revealed that female patients with localized colon cancer were significantly associated with p53 Pro72Pro genotype (4.0; 95% CI 1.27–12.7, p=0.04) whereas the cancer of rectosigmoid junction was associated with the EGF G61G genotype (4.5; 95% CI 1.2–16.97, p=0.02). Combination of p53 Arg72Pro or EGF A61G polymorphisms were not associated with CRC risk by using logistic regression.