DNA repair proteins maintain DNA integrity; polymorphisms in genes coding for these proteins can increase susceptibility to colorectal cancer (CRC) development. We analyzed a possible association of MLH1 -93G>A and 655A>G and XRCC1 Arg194Trp and Arg399Gln polymorphisms with CRC in Mexican patients. Genomic DNA samples were obtained from peripheral blood of 108 individuals with CRC (study group) at diagnosis and 120 blood donors (control group) from Western Mexico; both groups were mestizos. The polymorphisms were detected by PCR-RFLP. Association was estimated by calculating the odds ratio (OR). We found that the MLH1 and XRCC1 polymorphisms were in Hardy-Weinberg equilibrium. The MLH1 655A>G polymorphism in the 655G allele was associated with a 2-fold increase risk for CRC (OR = 2.04 and 95% confidence interval (95%CI) = 1.12-3.69; P < 0.01), while the MLH1 -93G>A polymorphism allele was associated with a protective effect (OR = 0.60, 95%CI = 0.40-0.89; P = 0.01 in the -93A allele and OR = 0.32, 95%CI = 0.13-0.79; P = 0.01 in the AA genotype). The XRCC1 Arg194Trp and Arg399Gln polymorphisms did not show any significant associations. In conclusion, we found that MLH1 -93G>A and 655A>G polymorphisms are associated with CRC in Mexican patients.Instituto de Genética Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México Laboratorio de Inmunobiología, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Zapopan, Jalisco, México Facultad de Medicina e Ingeniería en Sistemas Computacionales, Universidad de Tamaulipas, Matamoros, Tamaulipas, México Laboratorio de Genética Humana, Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Jalisco, México Departamento de Clínicas, Centro Universitario de Los Altos, Universidad de Guadalajara, Tepatitlán de Morelos, Jalisco, México