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ABSTRACTUnderstanding the mechanisms of chemoresistance in osteosarcoma (OS) cell is important for drug development. By establishment of cisplatin (CDDP) resistant OS cells, we found that the levels of visfatin in OS/CDDP cells were significantly greater than that in their parental cells. The CDDP resistant OS cells showed greater migration and invasion capability than that of parental cells. Knockdown of visfatin can rescue the CDDP sensitivity of resistant OS cells. Among the detected epithelial-mesenchymal transition-related transcription factors (EMT-TFs), visfatin can increase the expression of Snail and Zeb-1 in OS cells. Overexpression of Snail and Zeb1 can attenuate si-visfatin reduced CDDP resistance of OS cells. Mechanistical studies indicated that visfatin can increase the mRNA expression of Snail and therefore upregulate its expression via HIF-1α induced transcription. As to Zeb1, visfatin had no effect on its mRNA expression, while significantly increased its protein stability. Furthermore, the upregulation of ATM, which can phosphorylate and stabilize Zeb1, was involved in visfatin-induced Zeb1 expression in OS cells. Collectively, our revealed that visfatin was involved in CDDP resistance of OS cells via upregulation of Snail and Zeb1, suggesting that inhibition of visfatin might be a potential pathway for OS treatment.