Introduction: Multiple biologically relevant polymorphisms may have more accurate prediction of cancer prognosis compared with single polymorphism because of the modest effect. This study investigated whether the functional polymorphisms in P53 pathway genes, P53 Arg72Pro (rs1042522), P73 G4C14-to-A4T14 (rs2273953 and rs1801173), and MDM2 T309G (rs2279744), alone or in combination, affect survival in advanced non-small cell lung cancer (NSCLC) patients. Methods: A total of 199 stage III-IV NSCLC patients with platinum-based chemotherapy were recruited between 2002 and 2004. Associations between genotypes and survival were assessed using Kaplan-Meier method. Cox proportional hazard models were performed to identify significant variables. Results: During the median 26.5 months of follow-up, the P53 Pro/Pro genotype was strongly associated with shorter overall survival compared with the Arg/Arg genotype (12.0 versus 20.0 months; log-rank p = 0.002; hazard ratio = 1.86; 95% confidence interval [CI], 1.15-3.02). Pairwise combination analysis showed that patients carrying the variant P53 Pro/Pro-P73 GC/GC or P53 Pro/Pro-MDM2 GG genotypes had survival time only half of that for those carrying the wild-type genotypes, with hazard ratio being 2.47 (95% CI, 1.20-5.10) and 2.00 (95% CI, 1.15-3.46), respectively. Furthermore, a combined effect was seen with survival time being gradually shorter with increasing number of unfavorable genotypes in these three genes (ptrend = 0.039), indicating a gene-dose effect in association with survival. Conclusions: These findings suggest that genetic polymorphisms in the P53 pathway may be promising biomarkers for individualized chemotherapy and prognosis of NSCLC patients. Copyright © 2011 by the International Association for the Study of Lung Cancer.