PROSTAGLANDINS and glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism1,2. Two isoforms of the membrane protein COX are known3: COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins4; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells5, is responsible for the elevated production of prostaglandins during inflammation6,7. The structure of ovine COX-1 complexed with several NSAIDs has been determined8-10. Here we report the structures of unliganded marine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 Å resolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition.