Comparisons are made between the specific COX-2 inhibitors, celecoxib and rofecoxib, and acetaminophen. The specific COX-2 inhibitors are a significant advance in therapy because their anti-inflammatory, analgesic and antipyretic activities are associated with a high degree of gastrointestinal safety. Acetaminophen is often not considered to be a potent inhibitor of COX-2 but it is a potent inhibitor of prostaglandin synthesis in intact cells after stimulation by cytokines. Its weak activity on the pathway of prostanoid synthesis involving COX-1 is shown by its weak anti-platelet activity and good gastrointestinal safety. The specific COX-2 inhibitors and acetaminophen are analgesic after dental surgery, orthopedic surgery and in osteoarthritis although acetaminophen appears to be a slightly weaker agent. The apparent analgesic activity of both the COX-2 inhibitors and acetaminophen may, in part, be due to their anti-inflammatory properties. Both groups of drugs also decrease the urinary excretion of prostacyclin metabolites consistent with inhibition of the systemic and renal activity of the COX-2 system. During repeated dosage with the specific COX-2 inhibitors, the 24 hour urinary excretion of sodium is only inhibited for the first day of treatment while the excretion of sodium is still decreased over the first 3 hours after the individual doses. Therapeutic doses of the COX-2 inhibitors and overdoses of acetaminophen have been associated with the development of occasional cases of acute renal failure. Acetaminophen also may decrease the excretion of sodium and the reason for its greater renal safety at therapeutic doses is unclear. Myocardial infarction has also been attributed to the specific COX-2 inhibitors from meta-analysis of large scale clinical trials and examination of reports of adverse drug reactions although this is still a topic of considerable discussion. No such associations have been made with acetaminophen, possibly because it is a weak inhibitor of COX-1 in platelets.