OBJECTIVE: To determine the effect of dantrolene premedication on various cardiovascular and biochemical variables and recovery in isoflurane-anesthetized horses. ANIMALS: 6 healthy horses. PROCEDURES: Each horse was anesthetized twice with a 21- to 28-day washout period between anesthetic sessions. Food was not withheld from horses before either session. During each session, dantrolene (6 mg/kg in 2 L of water) or water (2 L) was administered via a nasogastric tube 1 hour before anesthesia was induced. Anesthesia was maintained with isoflurane for 90 minutes, during which blood gas analyses and lithium-dilution cardiac output (CO) measurements were obtained every 10 minutes. Serum creatine kinase activity was measured before and at 4, 8, and 12 hours after anesthesia. RESULTS: When horses were premedicated with dantrolene, CO at 25, 35, and 45 minutes after induction of anesthesia was significantly lower than that when horses were premedicated with water after which time difficulty in obtaining valid measurements suggested a continued decrease in CO; plasma potassium concentration progressively increased during anesthesia, whereas serum creatine kinase activity remained fairly stable and within reference limits through 12 hours after anesthesia; and 2 of 6 horses developed cardiac arrhythmias that required medical intervention. The quality of anesthetic recovery was slightly better when horses were premedicated with dantrolene versus water, although the time required for recovery did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that dantrolene premedication prevented muscle damage without affecting anesthetic recovery but impaired CO and precipitated hyperkalemia and cardiac arrhythmias in healthy isoflurane-anesthetized horses.