Anti-inflammatory effects of tocopherol (TOL) analogs have been attributed to their potent antioxidant activities. However, we and others have separately reported that γTOL or α-tocopheryl succinate (αTOS), despite their lower antioxidant activities, inhibit lipopolysaccharide (LPS)-induced production of prostaglandin E(2) (PGE(2)) in macrophages and lung epithelial cells more effectively than αTOL. In the present study, we sought to directly analyze the effect of three TOL analogs (αTOL, αTOS, and γTOL) on LPS-induced production of pro-inflammatory mediators in macrophages. Our data demonstrated that the inhibitory effects of all three TOL analogs on nitric oxide production were very limited. In contrast, αTOS dose-dependently and significantly inhibited LPS-induced PGE(2) production in both RAW264.7 cells and peritoneal macrophages, whereas αTOL and γTOL were much less effective. Although αTOS had no effect on LPS-induced cyclooxygenase-2 expression, it did inhibit COX activity in intact cells. αTOS in combination with sulforaphane, a compound that blocked LPS-induced COX-2 expression, cooperatively and more significantly inhibited PGE(2) production. These findings suggest that αTOS is a more potent inhibitor of the pro-inflammatory mediator PGE(2). The inclusion of αTOS in vitamin supplements may further enhance the effectiveness of strategies for preventing diseases associated with inflammation.