Abstract: Objective To investigate the mechanism of p38MAPK signal pathway on chemosensitivity of glioma drug-resistance cells. Methods After the U251/TMZ resistant glioma cell line was established,p38MAPK signaling pathway was blocked with the specific inhibitor SB203580. Cell activity was detected by MTT. Expression changes of MDR1, BCL-2 and TopoⅡ were detected by Western blot. Results The activity of drug-resistance cells was improved significantly after the signal pathway was blocked. With different concentrations of TMZ, the expression of BCL-2 and MDR1 were increased while TopoⅡ expression was decreased significantly in blocked group,compared with unblocked group, with significant difference (P＜0.05). Conclusion Blocked p38MAPK signaling pathway activates the chemosensitivity of glioma drug-resistance cells, and the mechanism may be related to the changes of MDR1, BCL -2 and TopoⅡ expression.