Purpose: Cyclooxygenase-2 (COX-2) plays important roles in the modulation of apoptosis, angiogenesis, immune response, and tumor invasion. Elevated COX-2 expression has been reported to be correlated with reduced survival after radiotherapy. This study examined whether genetic variations in the COX-2 gene are associated with different survival in inoperable locally advanced non-small cell lung cancer (NSCLC) treated with chemoradiotherapy or radiotherapy alone. Experimental Design: One hundred and thirty-six patients with inoperable stage IIIA-B NSCLC receiving thoracic irradiation between 2004 and 2007 were recruited in this study. Five functional COX-2 polymorphisms were genotyped using DNA from blood lymphocytes. Kaplan-Meier methods were used to compare survival by different genotypes. Cox proportional hazards models were used to identify independently significant variables. Results: During the median 22.4 months of follow-up, the favorable COX-2 -1195GA and GG genotypes were significantly correlated with better overall survival (20.2 months versus 15.7 months; P = 0.006; hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.39-0.86) and with longer progress-free survival (11.9 months versus 9.5 months; P = 0.034) compared with the -1195AA genotype. No significant associations were found among other COX-2 polymorphisms and clinical outcomes. In the multivariate Cox proportional hazards model, COX-2 -1195G/A polymorphism was independently associated with overall survival after adjusting the clinicopathologic factors (P = 0.008; HR, 0.58; 95% CI, 0.39-0.87). Conclusion: COX-2 -1195G/A polymorphism is a potential predictive marker of survival in locally advanced NSCLC patients treated with chemoradiotherapy or radiotherapy alone. ©2010 AACR.