Lung cancer is the leading cause of cancer mortality in the world. Although exposure to carcinogens is considered to be the main cause, genetic variation may contribute to lung cancer risk. Murine double minute 2, MDM2, is a key regulator of p53 activity and recently a polymorphism in the promoter region of the MDM2 gene was characterized. This single nucleotide polymorphism, SNP309, was shown to influence MDM2 transcription, MDM2 protein levels and p53 activity. The aim of this study was to investigate whether this functionally important SNP is associated with risk of nonsmall cell lung cancer. The study consisted of 341 nonsmall cell lung cancer cases and 412 healthy controls of Norwegian origin. Our results indicate that the G/G genotype of SNP309 is associated with lung cancer risk with an odds ratio of 1.62 (95% CI: 1.06–2.50). Interestingly, the strongest effect of the polymorphism was seen among women. Females homozygous for SNP309 G/G had associated odds ratio 4.06 (1.29–12.8). We also explored the MDM2 SNP309 in relation to TP53 gene mutations and age at nonsmall cell lung cancer diagnosis. Our results indicate that the G/G genotype of SNP309 is associated with higher age at diagnosis in individuals with TP53 mutations (p = 0.037). © 2006 Wiley‐Liss, Inc.