Six thoroughbreds were used in each of three trials to examine the effect of potassium depletion on exercise-associated muscle damage. Horses were exercised after a control period (Treatment 1), a 72-hour fast (Treatment 2), and furosemide and sodium bicarbonate (Treatment 3). During the preexercise period, feed withdrawal for 72 hours caused decreases in body weight, plasma sodium, chloride, and serum calcium. There were no changes in plasma potassium, erythrocyte potassium, or serum creatine phosphokinase (CK) activity. Furosemide and sodium bicarbonate administration resulted in a decrease in plasma potassium, chloride, serum calcium, and magnesium in the pre-exercise period. Erythrocyte potassium and serum CK activity were unchanged. Body weight initially decreased following furosemide and sodium bicarbonate and then increased upon access to water. In all three treatment groups plasma sodium, potassium, L-lactate, serum calcium, and magnesium were increased immediately following exercise. There was a significant increase (P less than 0.05) in serum CK activity in the furosemide and sodium bicarbonate-treated horses compared to control and withholding feed treatment groups by 30 minutes following exercise. Erythrocyte potassium was decreased immediately following exercise in the furosemide and sodium bicarbonate group but not in the other treatment groups. Potassium depletion may play a role in exercise-induced muscle damage but could not be implicated as the sole cause of the serum CK activity increase in this study.