Recent work indicates that pulmonary injury/capillary stress failure induced histamine release from airway inflammatory/mast cells may contribute to exercise-induced arterial hypoxemia (EIAH) in human subjects. Although exercising horses also exhibit EIAH and capillary stress failure induced exercise-induced pulmonary hemorrhage, the role of airway histamine release in causing EIAH remains unknown. Thus, we examined the effects of H₁ receptor antagonist, tripelennamine HCl, on EIAH in horses; the rationale being that pre-exercise antihistaminic administration may prevent histamine released from airway mast cells from exerting its effects on pulmonary capillary permeability, and thereby, attenuate/alleviate EIAH. Two sets of experiments, namely, placebo (saline) and antihistaminic (tripelennamine HCl @ 1.10 mg/kg, IV, 15 minutes pre-exercise) studies were carried out on 7 healthy, sound, exercise-trained Thoroughbred horses in random order, 7 days apart. In both treatments, arterial and mixed-venous blood-gas/pH measurements were made at rest before and after placebo/tripelennamine HCl administration, and during submaximal as well as maximal exercise performed at 14 m/s on a 3.5% uphill grade for 120s. Galloping at this workload elicited maximal heart rate and induced exercise-induced pulmonary hemorrhage in all horses in both treatments, thereby indicating that capillary stress failure related pulmonary injury had occurred. In both treatments, EIAH, desaturation of hemoglobin, hypercapnia, and acidosis of a similar magnitude developed during maximal exertion, and statistically significant differences between the placebo and antihistaminic studies could not be demonstrated. The failure of H₁ receptor antagonist to significantly modify EIAH suggests that pulmonary injury induced histamine release may not play a major role in bringing about EIAH in Thoroughbred horses.