Cyclooxygenase (COX) exists as constitutive (COX-1) and inducible (COX-2) isoforms. Nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and diclofenac inhibit both COX-1 and COX-2. The role of COX-2 in the genesis of fever in monkeys and humans was examined with use of the specific COX-2 inhibitor rofecoxib. Rofecoxib was administered to monkeys made febrile by 6 microg/kg intravenous lipopolysaccharide. Induced pyrexia was followed by oral rofecoxib (1 or 3 mg/kg), diclofenac (3 mg/kg), or vehicle. Rofecoxib and diclofenac rapidly reversed the elevated temperature (P < .05 versus vehicle for 3 mg/kg rofecoxib and diclofenac at 70 to 90 minutes after dosing). A single-dose, parallel-group, double-blind randomized trial was conducted in 94 patients with fever caused by a viral-type illness. Mean baseline temperature was similar for all groups (-38.5 degrees C). Patients received oral doses of 12.5 mg rofecoxib, 25 mg rofecoxib, 400 mg ibuprofen, or placebo and the mean +/- SE change in oral temperature at 4 hours after dosing was -0.97 degrees C +/- 0.11 degrees C, -1.19 degrees C +/- 0.09 degrees C, -1.20 degrees C +/- 0.11 degrees C, and 0.01 C +/- 0.17 C, respectively (P < .001 for active treatments versus placebo). Specific inhibition of COX-2 by rofecoxib results in antipyretic activity in monkeys and humans comparable to dual COX-1/COX-2 inhibitors such as diclofenac or ibuprofen. The data support the hypothesis that it is the COX-2 isoform that is primarily involved in the genesis of fever in humans.