Objective - To determine the effect of oral administration of dantrolene sodium on serum creatine kinase (CK) activity after exercise in horses with recurrent exertional rhabdomyolysis (RER). Animals - 2 healthy horses and 5 Thoroughbreds with RER. Procedure - 3 horses received 2 doses of dantrolene (4, 6, or 8 mg/kg, PO, with and without withdrawal of food) 2 days apart; 90 minutes after dosing, plasma dantrolene concentration was measured spectrofluorometrically. On the basis of these results, 5 Thoroughbreds with RER from which food was withheld received dantrolene (4 mg/kg) or an inert treatment (water [20 mL]) orally 90 minutes before treadmill exercise (30 minutes, 5 d/wk) during two 3-week periods. Serum CK activity was determined 4 hours after exercise. Plasma dantrolene concentration was measured before and 90 minutes after dosing on the first and last days of dantrolene treatment and before dosing on the first day of the inert treatment period. Results - 90 minutes after dosing, mean ± SEM plasma dantrolene concentration was 0.62 ± 0.13 and 0 μg/mL in the dantrolene and inert treatment groups, respectively. Serum CK activity was lower in dantrolene-treated horses (264 ± 13 U/L), compared with activity in water-treated horses (1,088 ± 264 U/L). Two horses displayed marked muscle stiffness on the inert treatment. Conclusions and Clinical Relevance - In 5 horses with RER from which food had been withheld, 4 mg of dantrolene/kg administered orally provided measurable, though variable, plasma concentrations and significantly decreased serum CK activity after exercise in 4 of those horses.