7221 Background: MDM2 is a negative regulator of p53. A T->G polymorphism in the promoter region of MDM2 has been described, where the G/G genotype is associated with higher MDM2 mRNA and protein levels. Overexpression of MDM2 is thought to interfere with p53-mediated apoptosis and growth inhibition, leading to cancer progression. We hypothesized that the MDM2 G/G genotype may be associated with worse survival outcomes in early stage lung cancer. Methods: We evaluated the relationship between MDM2 polymorphism status and overall survival (OS) and recurrence-free survival (RFS) among 385 Stage I and II NSCLC patients treated with surgical resection at Massachusetts General Hospital from 1992 to 2000. The MDM2 polymorphism was genotyped using the 5’-nuclease assay (Taqman). Kaplan-Meier methods and the log-rank test were used to compare survival by polymorphism status. Cox proportional hazards models were used to adjust for possible confounding variables. Results: Median age was 69, and 48% were female. 52% were Stage IA, 29% Stage IB, 4% Stage IIA, and 15% Stage IIB. 49% had adenocarcinoma, 29% squamous cell, 12% BAC, and 10% other NSCLC. The genotype frequencies for the MDM2 polymorphism were: T/T 161 (42%), T/G 156 (40%), G/G 68 (18%). Genotype was not associated with age, sex, stage, histology, or smoking status. Median follow-up time was 5.79 years. After adjusting for age, sex, stage, histology, and pack-yrs of smoking, the G/G genotype appeared to be associated with worse RFS and OS (AHR 1.60 (95% CI 1.10–2.34), p = 0.01; AHR 1.56 (95% CI 1.03–2.38), p = 0.04; respectively). In subset analysis, patients with squamous cell cancer and current-smokers had significantly worse survival with the G/G genotype, while there was no significant difference by genotype among adenocarcinomas and non-current smokers. (For squamous cell, 5-yr OS for T/T 59%, T/G 52%, G/G 7%, p = 0.0001; for current smokers, 5-yr OS for T/T 67%, T/G 49%, G/G 27%, p = 0.04). Conclusions: Our findings suggest that the G/G genotype of the MDM2 polymorphism is associated with worse survival among early stage NSCLC patients, particularly those with squamous cell histology and current smokers. Supported by NIH grants CA074386, CA092824, CA090578, FAMRI Young Clinical Scientist Award, Doris Duke Foundation. [Table: see text]