The effect of inhibition of cyclooxygenase activity on the hemodynamic response to exertion was examined in 6 horses. Rates of O2 consumption and CO2 production and carotid, pulmonary arterial, and right atrial pressures were measured while the horses performed a standardized exercise test on a treadmill after treatment with phenylbutazone or a placebo. Phenylbutazone (8.8 mg/kg p.o. for 2 days and 4.4 mg/kg i.v. 60 min before exertion) abolished the exertion-induced increases in plasma 6-ketoprostaglandin F1 alpha and thromboxane B2 concentrations, confirming inhibition of cyclooxygenase activity. Phenylbutazone treatment resulted in significantly (P < 0.05) higher heart rates and right atrial pressures during exertion than did treatment with placebo, which may have been due to increased myocardial sensitivity to sympathetic stimulation and/or decreased venous compliance. There was not a detectable effect of phenylbutazone on carotid or pulmonary arterial pressures, O2 consumption, CO2 production, or blood lactate concentration. Changes in plasma volume during exertion were not influenced by phenylbutazone. These results demonstrate that cyclooxygenase products likely mediate or modulate some of the systemic hemodynamic responses to exertion in horses.