The aim of this study was to assess whether the TP53 Arg72Pro polymorphism is associated with an increased risk of non-small cell lung cancer (NSCLC). Additionally, in NSCLC patients, we investigated a potential association between this polymorphism and somatic TP53 gene mutations in tumour cells. The study group included 240 NSCLC patients who underwent curative pulmonary resection. The control group (576 healthy subjects) was matched for sex and cigarette smoking. TP53 Arg72Pro polymorphism was determined by denaturing high-performance liquid chromatography. Tumours from 157 NSCLC patients were analysed for mutation in TP53 exons 5-8 by single strand conformation polymorphism, followed by sequencing of samples with different band pattern. Tumours from the remaining 83 patients were subjected to a direct sequencing of TP53 exons 5-8. The proportion of Pro homo/heterozygotes versus Arg homozygotes was significantly higher in NSCLC patients (54%) than in controls (46%, p = 0.034). The crude odds ratio for NSCLC development in Pro72 allele carriers was 1.39 (95% CI: 1.03-1.88). When adjusted for sex, age and smoking status in the multivariate logistic regression model, odds ratio for NSCLC development was 1.28 (95% CI: 0.91-1.80). Somatic TP53 mutations were found in 62 out of 240 NSCLC patients (26%), more frequently in Pro carriers (31%) than in Arg homozygotes (20%, p = 0.06). These results indicate that the TP53 codon 72 Pro allele may increase the risk of NSCLC. Additionally, the correlation between Pro72 and somatic TP53 mutations suggests that Pro72 allele carriers may be predisposed to tumour development along a p53 associated form of NSCLC, a finding that warrants further investigations.