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Purpose: To evaluate the efficacy and the safety profile of single-agent chemotherapy plus targeted agents compared with single-agent chemotherapy alone as second-line treatment for advanced Non-Small Cell Lung Cell (NSCLC).Methods: Published, randomized clinical trials were retrieved by searching the PubMed and EMBASE database.The pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), relative risks (RRs) for overall response rate (ORR) and grade 3/4 adverse events (AEs) were calculated by STATA package.Results: Six trials involving 2350 patients with advanced NSCLC after failure of first-line treatment were included.The overall results suggested that single-agent chemotherapy combined with targeted agents in second-line treatment could acquire more overall response (RR=1.86, 95% CI: 1.49-2.32,p< 0.001, p for heterogeneity (Ph) =0.620), longer PFS (HR=0.82, 95% CI: 0.75-0.89, p<0.001, Ph =0.380) and OS (HR=0.87, 95% CI: 0.78-0.97, p=0.012, Ph =0.786) than single-agent chemotherapy alone.Sensitivity analysis showed the same results when the meta-analysis was restricted to trials of epidermal growth factor receptor (EGFR) pathway targeted agents in combination, or to trials of vascular endothelial growth factor (VEGF) pathway targeted agents in combination.In the subgroup analysis according to chemotherapy regimens, both docetaxel and pemetrexed single-agent chemotherapies plus targeted agents could improve ORR (RR=1.73, 95% CI: 1.33-2.25, p<0.001, ph=0.646; RR=2.43, 95% CI: 1.57-3.76, p<0.001, ph=0.714, respectively).However, docetaxel plus targeted agents could improve PFS (HR=0.78, 95% CI: 0.70-0.87, p<0.001, ph=0.427) but not OS (HR=0.91, 95% CI: 0.80-1.04, p=0.159, ph=1.000), while pemetrexed plus targeted agents could improve OS (HR=0.81, 95% CI: 0.66-0.99, p=0.040, ph=0.621).The incidence of grade 3/4 AEs was similar in both arms.No publication bias was detected.Conclusions: The addition of targeted agents to single-agent chemotherapy regimens might improve the efficacy in the second-line treatment for advanced NSCLC, with similar toxicities.