OBJECTIVES: To compare the effectiveness of tyrosine kinase inhibitors gefitinib, erlotinib, or chemotherapy docetaxel/pemetrexed, for second-line treatment of advanced non-small-cell lung cancer (NSCLC) in Taiwan. METHODS: The Taiwan Cancer Registry, National Health Insurance claims database and Death Registry were obtained for newly diagnosed patients (≧18 years) with stage IIIB/IV NSCLC form 2007 to 2011, who received platinum-based chemotherapy as first-line therapy and were candidates for gefitinib, erlotinib and docetaxel/pemetrexed as second-line therapy. Patients were followed up until death or 2013 and assessed for overall survival (OS) and progression-free survival (PFS). Treatment efficacies were compared by the log-rank test in total population and subsets with different clinical characteristics. The Cox’s proportion hazard model was used to estimate the adjusted hazard ratios in multivariate analyses. RESULTS: A total of 4,757 patients, who received gefitinib (33.0%), erlotinib (34.6%) and docetaxel/pemetrexed (32.4%) for stage IIIB/IV NSCLC were included. Patients receiving gefitinib, erlotinib or docetaxel/pemetrexed had significantly different PFS (median: 14.97 vs 11.39 vs 9.95 months, P<.0001) and OS (median: 21.43 vs 16.26 vs 20.97 months, P<.0001). Compared to gefitinib, erlotinib had significantly higher risk of becoming progressive disease (adjusted HR: 1.25, 95% CI: 1.17-1.32; p<.0001) but similar in overall mortality (adjusted HR: 1.02; 95% CI: 0.94-1.10; p=0.629). Patients received docetaxel/pemetrexed had significantly high risk of becoming progressive disease (adjusted HR: 1.42; 95% CI: 1.31-1.53; p<.0001) and in overall mortality (adjusted HR: 1.27; 95% CI: 1.17-1.36; p<.0001). CONCLUSIONS: The post-hoc analysis illustrated real-world difference of treatment effectiveness in patients with advanced stage NSCLC who failed first-line platinum-based chemotherapy. The results found that second-line gefitinib therapy provided significantly prolonged PFS compared to second-line erlotinib and docetaxel/pemetrexed chemotherapy and significantly better OS compared to second-line docetaxel/pemetrexed chemotherapy.