Exercise increases mean body temperature (T_body) and cytokine concentrations in plasma. Cytokines facilitate prostaglandin (PG) production via cyclooxygenase (COX) enzymes, and PGE₂ 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. Methods: In a double-blind, cross-over design, 10 males (age 23 yr (SD 5); VO_{2 max} 53 ml.kg^-1.min^-1 (SD 5)) consumed Rofecoxib (50 mg.d^-1; NSAID) or placebo (PLAC) for 6 d, 2 wk apart. Exercising thermoregulation was measured on day 6 during 45-min treadmill running (~75% VO_{2 max}) followed by 45-min cycling and 60-min seated recovery (28°C, 50% rh). Plasma cytokine (TNF-, IL-10) concentrations were measured at rest and 30-min recovery. Results: T_body was similar at rest in PLAC (35.59°C) and NSAID (35.53°C) and increased similarly during running, but became 0.33°C (SD 0.26) lower in NSAID during cycling (37.39°C versus 37.07°C; P=0.03), and remained lower throughout recovery. Sweating was initiated at T_body of ~35.6^oC in both conditions but ceased at higher T_body in PLAC than in NSAID during recovery (36.66°C (SD 0.36) versus 36.39°C (SD 0.27); P=0.03). Cardiac frequency averaged 6 min^-1 higher in PLAC (P<0.01), whereas exercising metabolic rate was similar (505 versus 507 W.m^-2; P=0.56). A modest increase in both cytokines across exercise was similar between conditions. Conclusions: 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.