Studies have shown that TSPANI2 serves as an oncogenic gene or tumor suppressor depending on the types of cancer. However, its role in the drug resistance of small cell lung cancer (SCLC) is still unknown. In this study, we investigated whether TSPANI2 regulates chemoresistance, proliferation and tumor growth of SCLC under the regulation of miR-495 using two drug resistant cell lines. The results showed that down-regulation of TSPANI2 inhibited cells chemoresistance, proliferation and tumor growth. Besides, TSPAN12 elevation in SCLC specimens correlated with poor pathologic stage and shorter survival time. In addition, the dual luciferase assay indicated that TSPANI2 was one of the directly targeted genes of miR-495. Our study revealed that TSPANI2 promoted chemoresistance of SCLC under the regulation of miR-495. TSPANI2 depletion is a promising strategy for inhibiting the chemoresistance in SCLC. (C) 2017 Published by Elsevier Inc.