The aim of this study was to evaluate the efficacy and safety of gefitinib as a first-line therapy for advanced non-small cell lung cancer (NSCLC). Patients with advanced NSCLC who did not tolerate or who refused chemotherapy received 250 mg/day of gefitinib orally as first-line therapy. A total of 68 NSCLC patients were enrolled, and the overall response rate (RR) and disease controlled rate (DCR) with gefitinib treatment was 35.3 and 77.9%, respectively. The median progression-free survival (PFS) was 6.6 months and the median survival was 15.5 months. The median PFS of the adenocarcinoma patients and the non-smokers was significantly longer compared to that of the non-adenocarcinoma patients and the smokers (P<0.05). The median survival of the patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 was significantly longer compared to that of the patients with PS ≥2 (P<0.05). The most common side effects of gefitinib treatment were mild rash and diarrhea. Therefore, first-line therapy with gefitinib is an effective and tolerable treatment regimen for advanced NSCLC.