Background and objective The e?cacy of second or third-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients is low. The use of targeted drugs brings survival benefit for some patients. Apatinib, as a novel small molecule antiangiogenic drug, has demonstrated satisfactory anticancer activity across a broad range of malignan-cies. The aim of this study is to evaluate the e?cacy and safety of apatinib in patients with advanced NSCLC after first-line treatment failure. Methods A retrospective study of 128 patients was conducted to evaluate the safety, short-term e?cacy and survival status with different regimens. Kaplan-Meier method and Cox regression model were used for analysis. Results Compared with chemotherapy alone, the median progression free survival (PFS) in apatinib monotherapy, chemotherapy alone and apatinib combined with chemotherapy were 3.0 (P=0.381), 3.7 and 6.0 months (P<0.001), respectively. The me-dian overall survival (OS) were 6.0 (P=0.494), 6.5 and 9.0 months (P=0.001), respectively. The incidence of adverse events in grades 3-4 were 18.5%, 15.8% and 16.0%, respectively (P=0.947). Different treatment regimens (P=0.018) and performance status (PS)(P<0.001) were the independent factors of PFS. The smoking history (P=0.014), treatment regimens (P=0.002) and PS (P<0.001) were independent influencing factors of OS. Conclusion Apatinib has a good security. After first-line treat-ment failure of lung cancer, chemotherapy combined with apatinib in second or third-line is beneficial in PFS and OS when compared with chemotherapy alone. But when making comparison between apatinib monotherapy and chemotherapy alone,there is no significant difference in PFS and OS. Patients who never smoke or has a better PS or use combination therapy have longer survival time.