Germline mutations or the malfunctioning of postreplicative mismatch repair genes (MMR) are responsible of hereditary nonpolyposis colorectal cancer (HNPCC), and are also implied in some sporadic colorectal cancer (CRC) forms without any familial history of this disease. Besides germinal mutations and methylation, single-nucleotide polymorphisms (SNP) can predispose to nonfamilial CRC with low to moderate penetrance. In this case-control study, we analyzed three MLH1 single-nucleotide polymorphisms (exon 5: 415G-->C, rs28930073; exon 8: 655A-->G, rs1799977 and exon 16: 1852-1853AA-->GC) in 140 sporadic colorectal cancer cases and 125 healthy individuals to evaluate the relationship among CRC risk and clinicopathologic and genetic characteristics of the tumors. In our study, no 415G-->C variant carrier was found among all analyzed samples. The 1852-1853AA-->GC is a rare variant detected in heterozygoses in five controls and one case. In relation to the more frequent 655A-->G polymorphism, association analyses revealed that G carriers (AG or GG genotype) displayed a higher risk of CRC compared with AA homozygous [odds ratio (OR) AG=2.55, 95% confidence interval (CI)=1.48-4.39; P=0.01 and OR GG=2.48, 95% CI=1.20-5.11; P=0.01, respectively]. G-carrier males showed high CRC risk compared with homozygous AA wild-type individuals (OR: AG=3.05; 95% CI=1.49-6.26, P=0.002; OR: GG=3.60; 95% CI=1.29-10.03). Nevertheless, patients carrying the G allele displayed a better outcome than wild-type genotype carriers (log rank=7.26; P=0.007) and did not present vascular invasion (P=0.03), distant metastasis (P=0.004), or recurrence (P=0.01). MLH1 655A-->G change is associated with an increased risk, although it seems to have a favorable effect on patients, providing a better outcome. Moreover, our results suggest that for genomic profiling to predict the clinical outcome of patients with colorectal cancer, gender must also be considered.