Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been extensively investigated in previously treated advanced non-small-cell lung cancer (NSCLC), but what it is still unclear is the efficacy of (EFGR-TKIs: gefitinib or erlotinib) monotherapy in previously treated non-small-cell lung cancer (NSCLC). In December 2013, we performed a search in the PubMed, EMBASE, Cochrane library databases and Web of Science for randomized trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through strict inclusion and exclusion criteria, fourteen trials (three front-line, two second-line, nine maintenance, n = 8970 patients) were eligible. EGFR-TKIs significantly increased overall survival (OS) [hazard ratio (HR) 0.88, 95%confidence interval (CI) 0.82-0.96, I (2) = 50.5%] and progression-free survival (PFS) (HR 0.71, 95% CI 0.63-0.81, I (2) = 81.2%] compared with placebo or best support care (BSC). Patients with clinical features such as never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced OS and PFS benefit. The main adverse reactions were diarrhea, rashes, anorexia and anemia, [odds ratio (OR) = 3.635, 95% confidence interval (CI) = (2.377 to 5.557)], [OR = 15.664, 95%CI = (8.869 to 27.665)], [OR = 1.555, 95%CI = (1.060 to 2.283)], [OR = 1.481, 95%CI = (1.114 to 1.969)], respectively. The results show that monotherapy therapy with EFGR-TKIs produce a significant OS and PFS benefit for patients with NSCLC compared with placebo or BSC, especially for the patients who had adenocarcinomas, non-smokers and patients with EGFR gene mutations.