A single-nucleotide polymorphism (SNP) in the promoter of the MDM2 gene, SNP309 (a T-->G change), was recently implicated in the early onset of cancer in individuals with Li-Fraumeni syndrome and of sporadic soft-tissue sarcoma. SNP309 induces an increase in the level of Mdm2 protein, which causes attenuation of the p53 pathway. To investigate the effect of this polymorphism in colorectal cancer pathogenesis, we genotyped 153 colorectal cancer patients who were randomly selected from among 330 consecutive patients stratified according to p53 mutation status and age at diagnosis, for alleles of MDM2-SNP309. Among the 77 patients with p53 wild-type tumors, the median age at colorectal cancer diagnosis was 71.5 years for patients with the T/T genotype and 61.0 years for patients with SNP309 (T/G or G/G genotype) (estimated difference between medians [Hodges-Lehmann method] = 8.0 years, 95% confidence interval = 1.0 to 16.0 years; P = .03 [two-sided Wilcoxon rank sum test]). Our data indicate that MDM2-SNP309 is a modifier of the age at colorectal cancer onset for patients whose tumors have a wild-type p53 gene.