Tocopherol analogs are known to have pleiotropic effects due to its interaction with diverse intracellular targets. Previously we reported that low_{apoptotic dose of ${alpha}$<}-tocopheryl succinate (${alpha}TOS$) inhibits cyclooxygenase (COX) and prostaglandin $E_2$ ($PGE_2$) production in lung epithelial cells, while high dose of ${alpha}TOS$ induces the reactive oxygen species (ROS) generation and apoptosis. In our separate study, we demonstrated that ${alpha}$-tocopheryl polyethylene glycol succinate (${alpha}TPGS$), a polyethylene glycol (PEG)-conjugated derivative of ${alpha}TOS$, is a more potent ROS/apoptosis inducer compared with ${alpha}TOS$. The present study was prompted to examine whether PEG conjugation to ${alpha}TOS$ also enforced its COX inhibitory activity. Of interest, we found that ${alpha}TPGS$ failed to inhibit COX activity regardless of doses, suggesting that PEG conjugation to ${alpha}TOS$ resulted in the loss of its COX inhibitory activity. Unexpectedly, ${alpha}TPGS$ rather induced the COX-2 protein expression at higher/apoptotic doses. ${alpha}TPGS$-induced COX-2 expression was inhibited by antioxidant pretreatment. These data indicate that the COX-2 induction by ${alpha}TPGS$ is mediated through increased ROS generation. Since the use of ${alpha}TPGS$ as a surfactant component of dispersive drug delivery systems is frequently considered, caution should be taken when the drugs involved in COX signaling are loaded in ${alpha}TPGS$-included delivery systems.