The present study aimed to investigate the regulatory mechanisms by which interleukin (IL)-22 regulates cisplatin (DDP) sensitivity in osteosarcoma cells. Firstly, reverse transcription-quantitative (RT-q) PCR and western blotting demonstrated that IL-22 expression was significantly increased in osteosarcoma tissues and cell lines compared with the adjacent normal tissues and the normal osteoblast hFOB1.19 cells. Subsequently, the MG63 osteosarcoma cell line and cisplatin-resistant MG63/DDP osteosarcoma cell line were treated with different concentrations of cisplatin (2.5, 5.0, 10, 20, 40 and 80 µg/ml), and the half maximal inhibitory concentration (IC50) was calculated based on the MTT assay. The results showed that the IC50 of DDP in MG63/DDP cells was significantly higher than that in MG63 cells. Furthermore, IL-22 expression was higher in MG63/DDP cells compared with MG63 cells. Subsequently, the effects of IL-22 downregulation and overexpression on MG63/DDP and MG63 cells were assessed using the MTT assay, flow cytometry, RT-qPCR and western blotting. The IL-22 small interfering (si) RNA in MG63/DDP cells significantly decreased the IC50 of DDP and decreased the cell viability of MG63/DDP cells. Furthermore, IL-22 RNA interference decreased BCl-2 expression and phosphorylation of STAT3, induced apoptosis, and increased the expression of Bax and cleaved caspase-3. The IL-22 overexpression plasmid had opposite effects to the observations in IL-22 siRNA-transfected MG63 cells. Overall, the present study indicated that IL-22 regulated the cell viability and apoptosis of osteosarcoma cells by regulating the activation of the STAT3 signaling pathway and affecting the expression of apoptosis-associated genes, and thereby mediating the sensitivity of osteosarcoma cells to cisplatin.,Copyright: © Li et al.