TP53 is well-recognized as a mutational target in cancers and common variation in the TP53 gene has been investigated as potentially contributing to cancer susceptibility. The codon 72 polymorphism has been proposed to alter the phenotype of TP53 mutations, and TP53 mutations have been reported to occur preferentially on the arginine allele. Using a consecutive case series of non-small cell lung cancer we have investigated whether TP53 mutations occur preferentially on the arginine or proline allele, and whether the combination of mutation and allelism confers differences in the clinical phenotype. The overall prevalence of TP53 mutation was 26% (76/293). The majority of mutations occurred on the arginine allele (51/60, 85%), and there was corresponding strong selection for loss of the proline allele [87% of loss of heterozygosity (LOH) events were loss of proline]. However, there was no statistically significant difference in the prevalence of mutation by constitutional genotype and among heterozygotes with LOH, TP53 mutation prevalence did not differ by the codon 72 polymorphism (48% on arginine versus 40% on proline). Importantly, patient survival did significantly differ: those patients having a TP53 mutation on the proline allele had the worst survival outcomes (hazards ratio = 2.6, P < 0.03). Further, this phenotype was limited to those patients with advanced disease, where mutation on the proline allele was associated with a significantly worse outcome compared with those without mutation or with mutation on the arginine allele (P < 0.001). Our data suggest that there are selective pressures for loss of the TP53 proline allele in non-small cell lung cancer. Further, the combination of mutation with the codon 72 proline variant predicts poorer patient survival, particularly in a disease that has progressed outside the lung, a finding that warrants further investigation.