Rofecoxib is a commonly used specific cyclo-oxygenase-2 (COX-2) inhibitor. Rofecoxib has high bioavailability, poor aqueous solubility, an elimination half-life suitable for daily administration and a volume of distribution approximating body mass. Species-specific, predominantly hepatic, metabolism occurs, with novel enterohepatic circulation in rats and O-glucuronidation by uridine diphosphate-glucuronosyl transferase (UGT) 2B7 and 2B15 in human liver microsomes. Discrepancies in studies of postoperative analgesia can be putatively explained by known pharmacokinetics. Changes in rofecoxib disposition and pharmacokinetics are evident between races, in elderly patients, in patients with chronic renal insufficiency and in patients with mild to moderate hepatic impairment. Despite the selective action of COX-2 inhibitors, there remains the potential for significant drug interactions. Rofecoxib has been shown to have interactions with rifampicin (rifampin), warfarin, lithium and angiotensin converting enzyme (ACE) inhibitors and theophylline. COX-2 inhibitors represent a major therapeutic advance in terms of gastrointestinal safety; however, long-term safety in other organ systems and with concomitant drug administration still remain to be proven.