Background: Apatinib is an oral, small molecular tyrosine-kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR). Phase II study has showed that apatinib significantly improved the outcome of patients with advanced or metastatic gastric cancer (Li J, et al. ASCO 2011). The primary object of this study is to determine whether apatinib can improve progression free survival (PFS) compared with placebo in patients with advanced non-squamous NSCLC who failed two lines of treatment. Methods: This study recruited histologically diagnosed advanced non-squamous NSCLC patients who failed more than two lines of treatment including EGFR TKIs. Other eligible criteria included ECOG ≤1, adequate organ function and no prior exposure to VEGFR-TKI. The patients were randomized to receive apatinib at a dose of 750 mg or placebo (at allocation ratio of 2:1) orally once daily until the disease progression or unacceptable toxicity. Results: 135 patients (90 in apatinib arm, 45 in placebo arm) were included at 20 centers in China until Aug 2011. Median PFS was 4.7 months for apatinib group versus 1.9 months for placebo group, hazard ratio (HR) was 0.278 (95% CI 0.170, 0.455) (p<0.0001). The response rate (RR) and disease control rate (DCR) were also significantly better in study arm (12.2% and 68.9%) than in placebo arm (0% and 24.4%)(P=0.0158 and P<0.0001). The most frequently observed AEs were hypertension, proteinuria, and hand-foot syndrome (HFS). These AEs were generally mild or moderate in severity and were manageable. Conclusions: This randomized phase II trial shows that apatinib has substantial clinical activity without significant additional toxicity in patients with advanced non-squamous and non-small cell lung cancer. Continued investigation of apatinib is warranted in future clinical studies.