Dexamethasone (DEX) has been frequently used as a co-medication in cytotoxic cancer therapy, mostly for supportive care in alleviating the acute toxic effects on healthy tissues. Although recent studies have demonstrated DeXinduced resistance to cytotoxic treatment in several solid tumors, no specific molecular mechanism of action has been reported. Here, we assessed the effect of DEX on the cisplatin-induced cytotoxicity in fresh surgically resected specimens from Chinese patients with lung cancer. We also examined the effects of DEX and cisplatin on the apoptotic signaling pathway in the well-established human lung adenocarcinoma cell line A549. Our results show that DEX treatment inhibits cisplatin-induced cell apoptosis by up-regulation of cellular mitogen-activated protein kinase phosphatase-1 (MKP-1) and subsequent deactivation of p38 protein kinase. Knock down of MKP-1 by RNA interference reversed the DEX-induced inhibition of cisplatininduced cell apoptosis. These data suggest that administration of DEX during the clinical therapy of Chinese lung cancer patients must be carefully considered, and indicate that MKP-1 and p38 protein kinase are potential targets for DEX-induced drug resistance.