Background: Information on the optimal therapy beyond the second-line treatment of small cell lung cancer (SCLC) is very limited and controversial. Inhibiting the components of the VEGF signaling pathway is an attractive treatment option for SCLC patients. Apatinib, a selective inhibitor of VEGF receptor-2 (VEGFR-2) tyrosine kinase, has been proven to be safe and effective for the treatment of a broad range of advanced solid tumors. In our prospective clinical study, we aim to evaluate the efficacy and safety of single-agent apatinib as treatment of extensive-stage (ES) SCLC patients after failure from at least two prior chemotherapy regimens. Methods: Twenty-two ES-SCLC patients treated with single-agent apatinib after failure from at least two prior chemotherapy regimens in our institution between November 2016 to August 2018 were enrolled in the clinical study. Apatinib mesylate was orally administered at a dose of 500 mg once daily on a 28-day cycle until evaluation of disease progression (PD) or the occurrence of unacceptable toxicity. Dosage reduction to either 425 mg or 250 mg once daily were permitted based on the evaluation of toxicities. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and adverse events (AE). Results: The median age was 56 years, ranging from 36 to 70 years. A majority (63.6%, 14/22) received apatinib as third-line treatment, while 22.7% (5/22) and 13.6% (3/22) received it as fourth or fifth-line treatment, respectively. Partial response (PR) was achieved by 3 (13.6%) patients and stable disease exhibited by 18 (81.8%) patients. The median PFS and OS were 5.4 and 10.0 months, respectively. Apatinib demonstrated a manageable toxicity profile, with grade I-III secondary hypertension and proteinuria as the most common AE. Grade III adverse events were only observed in 3 (13.6%) patients with either hypertension (1 patient) or proteinuria (2 patients). Except for these 3 patients, all the other patients experienced grade I-II adverse events. No grade IV and V AE were observed among the patients. Multivariate analysis revealed secondary hypertension as an independent predictor of OS (p= 0.047). Conclusions: Apatinib is safe and effective in the management of ES-SCLC patients and can be considered as a treatment option after failure from at least two prior chemotherapy regimens. Secondary hypertension can be a potential prognostic factor for apatinib treatment. Clinical trial information: NCT02995187