It is apparent that lung cancer is associated with inflammation, with accompanying hallmark elevations of cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) levels. However, the effects of these changes on MRP efflux transporters have not been thoroughly investigated before. Here, we report that upregulation of COX-2 can induce overexpression of MRP4 in both A549 non-small-cell lung cancer cell lines and mouse lung cancer models. In A549 cells, phorbol 12-myristate 13-acetate (PMA) treatment induced upregulation of COX-2 and MRP4 together, but not other MRP transporters. Transient overexpression of human COX-2 cDNA also specifically increased COX-2 and MRP4. Moreover, COX inhibitor treatment and COX-2-specific siRNA significantly inhibited the upregulation of MRP4. Additionally, PMA-treatment increased extracellular PGE2 levels, likely due to increased MRP4 function. Likewise, COX-2-specific siRNA reduced extracellular PGE2 levels. Furthermore, COX-2 upregulation resulted in an increase in mPGES-1, an enzyme responsible for PGE2 production. Finally, metastasized lung cancer model mice exhibited increased expression levels of COX-2 and MRP4, as well as mPGES-1. In conclusion, the present study suggests that overexpression of MRP4 in lung cancer may be attributable to COX-2 upregulation via a PGE2-dependent pathway.