Objective The objective of this study was to investigate the inhibitory effect of MDM2 inhibitor Nultin-3 com-bined with cisplatin on human oral squamous cell carcinoma(OSCC)Tca8113 cells and its mechanism. Methods Human OSCC Tca8113 cells were treated with Nultin-3,cisplatin,Nultin-3 combined with cisplatin,or vehicle control groups. The proliferation of Tca8113 cells was determined by thiazolyl blue(MTT)assay. The expression of MDM2,P53,Caspase-9 and Caspase-3 protein was determined by Western blot. Results The proliferative rate of OSCC ca8133 cells treated with Nultin-3 combined with cisplatin was significantly lower than that of other groups(P<0. 05). The relative expression of Caspase-9,Caspase-3 and P53 protein in the Nultin-3 combined with cisplatin was significantly higher than those of the Nultin-3 and cisplatin alone groups(P<0. 05). In addi-tion,the relative expression of MDM2 protein in the Nultin-3 combined with cisplatin group was significantly lower than that of the cisplatin and Nultin-3 alone groups(P<0. 05). Conclusion Nultin-3 combined with cisplatin has synergistic effect on oral squa-mous cell carcinoma Tca8113 cells. Nultin-3 regulates the MDM2-p53 signaling pathway and up-regulates the expression of pro-apoptotic proteins Caspase-9 and Casapase-3 to enhance the inhibition of cisplatin on oral squamous cell carcinoma,providing a solid theoretical basis for clinical research and treatment.