Antagonism of ketamine-xylazine (85 mg of ketamine/kg of body weight and 15 mg of xylazine/kg, IM) anesthesia in rats by yohimbine (YOH; 1, 5, 10, and 20 mg/kg, IP), tolazoline (TOL; 10, 20, or 50 mg/kg, IP), 4-aminopyridine (4-AP; 1 or 5 mg/kg, IP), or a combination of yohimbine and 4-aminopyridine (YOH:4-AP, 1 mg/kg:1 mg/kg or 5 mg/kg:1 mg/kg, IP) was studied. All dosages of YOH, TOL, 4-AP, and YOH:4-AP reduced the time to appearance of corneal and pedal reflexes. Only TOL was effective in reducing time to appearance of the crawl reflex and recovery time. Yohimbine, 4-AP, YOH:4-AP, and TOL were effective in reversing respiratory depression caused by ketamine-xylazine anesthesia, but anesthetic-induced hypothermia was not antagonized. When given to non-anesthetized rats, the antagonists had little influence on respiratory rate, but all antagonists caused significant (P less than 0.05) reduction in core body temperature for at least 90 minutes. When YOH was used as an anesthetic antagonist at dosage of 20 mg/kg, 20% mortality was observed and was attributable to acute respiratory arrest. The use of 4-AP and YOH:4-AP at the dosages studied induced moderate to severe muscular tremors. In conclusion, TOL at dosage of 20 mg/kg given IP, appears to be an appropriate antagonist for ketamine-xylazine anesthesia in rats.