Abnormalities of the tumor suppressor TP53 pathway are critical in the development of many cancers since it regulates cell cycle components and apoptosis. Murine double minute‐2 (MDM2) protein is a central node in the p53 pathway and a direct negative regulator of p53. The MDM2 SNP309 (rs2279744) polymorphism increases MDM2 RNA and protein levels, attenuating the p53 pathway. The MDM2 SNP309 polymorphism was investigated in 1,787 Caucasian nonsmall cell lung cancer (NSCLC) patients and 1,360 healthy controls. Cases and controls were analyzed for associations with genotype and adjusted for age, gender, histology and smoking history. There were no overall associations between the MDM2 genotypes and risk of lung cancer (adjusted odds ratios [AORs] = 0.82 [95% confidence interval [CI] = 0.6–1.1] for the T/G genotype and AOR = 1.32 [95% CI = 0.9–2.0] for the G/G genotype). A statistically significant interaction (p = 0.01) was found between smoking and MDM2 genotypes. Consistent with this interaction, stratified analysis by pack‐years of smoking demonstrated that the AORs of G/G vs. T/T were 1.56 (1.0–2.7), 1.46 (1.0–2.2), 0.80 (0.5–1.3) and 0.63 (0.4–1.1), respectively, for never, mild (<30 pack‐years), moderate (30–57 pack‐years) and heavy smokers (≥58 pack‐years). In conclusion, a strong gene‐smoking interaction was observed between the MDM2 SNP309 and NSCLC risk. © 2007 Wiley‐Liss, Inc.