OBJECTIVES: Lung cancer is the first cause of cancer death in both men and women worldwide and 85% are NSCLC. As a targeted therapy for NSCLC, EGFR-TKIs has been compared with traditional chemotherapy in various trials in different countries but there is a lack of comprehensive literature review of these RCTs especially from Health-Related Quality of Life (HRQoL) perspective. We compared the efficacy, safety and HRQoL between EGFR-TKIs(gefitinib, erlotinib and afatinib) and chemotherapy for advanced NSCLC patients with largest magnitude.  METHODS: Two authors independently searched published RCTs comparing EGFR-TKIs vs chemotherapy for advanced NSCLC between Jan 1, 1966 and July 31, 2013 in PubMed, Cochrane Library, EMBASE, the conference proceedings of ASCO and ESMO. We conducted meta-analysis by Revman 5.0 using either random or fixed effects inverse variance weighted method, determined by heterogeneity levels.  RESULTS: Twenty-two eligible studies and 6728 patients were included. Comparing to chemotherapy, EGFR-TKIs were superior in objective response rate (OR=1.90, 95% CI=1.32-2.57, P<0.00001) and progression free survival (HR=0.78, 95%CI= 0.66-0.91, P<0.00001). However, no significant differences were observed on disease control rate (OR: 1.24; 95% CI=0.89-1.73), median overall survival (HR=1.00; 95%CI= 0.93-1.07) and 1-yr survival rate (OR=0.96; 95% CI = 0.82-1.13). EGFR-TKIs demonstrated less adverse events in neutropenia (OR=0.01, 95% CI=0.01-0.02), anemia (OR=0.2, 95% CI=0.14-0.31), fatigue (OR=0.18, 95% CI=0.12-0.29) and nausea (OR=0.35, 95% CI=0.21-0.60) and less grade 3 or 4 adverse events (OR=0.29, 95%CI=0.26-0.33). However, chemotherapy had less rash (OR=7.18, 95% CI=4.67-11.05) and diarrhea (OR=2.10, 95% CI=1.49-2.98). In 8 studies evaluating the HRQoL, EGFR-TKIs had shown better outcomes than chemotherapy according to the three HRQoL instruments: Functional Assessment of Cancer Therapy-Lung (OR=1.62, 95% CI=1.38-1.91), Trial Outcome Index (OR=1.93, 95%CI=1.61- 2.33), and Lung Cancer Subscale (OR=1.19, 95%CI=1.01-1.39).  CONCLUSIONS: Though no obvious survival benefit was observed, EGFR-TKIs demonstrated significantly better safety and HRQoL outcomes than chemotherapy.