Exercise increases mean body temperature (T(body)) and cytokine concentrations in plasma. Cytokines facilitate PG production via cyclooxygenase (COX) enzymes, and PGE(2) can mediate fever. Therefore, we used a COX-2 inhibitor to test the hypothesis that PG-mediated pyrogenicity may contribute to the raised T(body) in exercising humans. In a double-blind, cross-over design, 10 males [age: 23 yr (SD 5), Vo(2 max): 53 ml x kg(-1) x min(-1) (SD 5)] consumed rofecoxib (50 mg/day; NSAID) or placebo (PLAC) for 6 days, 2 wk apart. Exercising thermoregulation was measured on day 6 during 45-min running ( approximately 75% Vo(2 max)) followed by 45-min cycling and 60-min seated recovery (28 degrees C, 50% relative humidity). Plasma cytokine (TNF-alpha, IL-10) concentrations were measured at rest and 30-min recovery. T(body) was similar at rest in PLAC (35.59 degrees C) and NSAID (35.53 degrees C) and increased similarly during running, but became 0.33 degrees C (SD 0.26) lower in NSAID during cycling (37.39 degrees C vs. 37.07 degrees C; P = 0.03), and remained lower throughout recovery. Sweating was initiated at T(body) of approximately 35.6 degrees C in both conditions but ceased at higher T(body) in PLAC than NSAID during recovery [36.66 degrees C (SD 0.36) vs. 36.39 degrees C (SD 0.27); P = 0.03]. Cardiac frequency averaged 6 x min(-1) higher in PLAC (P < 0.01), whereas exercising metabolic rate was similar (505 vs. 507 W x m(-2); P = 0.56). A modest increase in both cytokines across exercise was similar between conditions. COX-2 specific NSAID lowered exercising heat and cardiovascular strain and the sweating (offset) threshold, independently of heat production, indicating that PGE-mediated inflammatory processes may contribute to exercising heat strain during endurance exercise in humans.