High level of mitogen-activated protein kinase phosphatase-1 expression is associated with cisplatin resistance in osteosarcoma. Cisplatin is one of the most effective chemotherapeutic agents in the treatment of several solid tumors including osteosarcoma (OS). Despite aggressive treatment, 25% of patients with OS continue to die from their disease. Since cisplatin based regimens have been uniformly used in OS therapy, treatment failure is likely due, at least in part, to cisplatin resistance.The objective of this study was to determine the relationship between MKP-1 expression and cisplatin sensitivity of OS cell lines and to explore the mechanism underlying this relationship. Three OS cell lines were examined for their MKP-1 expression and cisplatin sensitivity. JNK phosphorylation and apoptosis induction was also measured. Western and Northern blot, flow cytometry, siRNA, and MTT assays were used.U2OS cells, which express high level of MKP-1, are less sensitive to cisplatin-induced cell death. Inhibition of MKP-1 by siRNA silencing sensitizes U2OS cells to cisplatin-induced cell death. Furthermore, delayed apoptosis induction following cisplatin treatment was observed in U2OS, in parallel to decreased JNK activation, increased MKP-1 expression and relatively increased cisplatin resistance. Interestingly, triptolide, an MKP-1 inhibitor, blocks MKP-1 expression and enhances cisplatin-induced cell death.High MKP-1 expression is associated with decreased sensitivity or increased resistance to cisplatin-induced cell death in OS cell lines, and MKP-1 could potentially be used as a marker of cisplatin resistance and a therapeutic target for molecular therapies.