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Objective: To evaluate the efficacy and safety of celecoxib plus platinum-doublet as first-line chemotherapy in treatment of advanced non-small cell lung cancer (NSCLC), and to determine the subgroup benefiting from celecoxib combined therapy by molecular analysis. Methods: A total of 44 treatment-naive patients of advanced NSCLC with positive cyclooxygenase-2 (COX-2) expression confirmed by immunohistochemical (IHC) staining were designed to receive celecoxib plus platinum-doublet chemotherapy (cisplatin plus gemcitabine, novelbine or docetaxol) from February 2005 to May 2007. On 5(7 day before chemotherapy, 400 mg celecoxib was administered twice a day orally until obvious evidence of disease progression or intolerable toxicity was found. Adverse events were recorded according to NCI-CTC criteria. The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), 1-year survival rate, response rate (RR) and safety. Additionally, we detected epithelial growth factor receptor (EGFR) status including EGFR gene amplification by real-time PCR and gene mutations by DHPLC followed by sequencing. Results: The response rate was 45% (20/44), and the disease control rate (DCR) was 59% (26/44). The median progression-free survival time and median survival time were 6 m and 18 m, respectively. The 1-year survival rate was 68%. Chemotherapy cycle numbers and best response were found to be the predictive factors for PFS by COX model analysis (P=0.023 and P=0.000, respectively). No factor was found to affect OS. The most common toxicities included neutropenia and nausea/vomit. EGFR gene amplification was an independent prognostic factor influencing OS (P=0.0002). Patients with EGFR mutations (exon 21) had a tendency of disease progression (P=0.041). Conclusion: Encouraging activities of celecoxib combined with platinum-doublet chemotherapy were demonstrated in treatment-naive patients with advanced NSCLC, with good tolerances. For COX-2 IHC positive patients, positive EGFR amplification and mutation might be related to poor clinical outcomes.