Mutations in the TP53 gene are important events during human lung carcinogenesis. The TP53 gene harbors several polymorphisms, and functional studies have shown that the Arg72Pro polymorphism alters both wild-type and mutant p53 protein activity. Thus, we hypothesized that certain Arg72Pro genotypes may influence the frequency and pattern of somatic mutations in TP53. We therefore examined the status of the Arg72Pro polymorphism and TP53 mutations in 260 non-small-cell lung cancer cases. Here we report a significant trend toward lower frequency of TP53 mutations with increasing number of Pro72 alleles (P = 0.02). Overall, Pro72 allele carriers had significantly lower frequency of TP53 mutations compared with Arg72 homozygotes (P = 0.02). In addition, carriage of the Pro72 variant was related to a lower frequency of mutations affecting the hotspot codon 273. Mutations at codon 273 accounted for 10.6% of the mutations in Arg72 homozygotes and 1.7% of the mutations in Pro72 allele carriers. Our results suggest that the genotype of the Arg72Pro polymorphism may modulate the frequency of TP53 mutations in non-small-cell lung cancer.