We compared ketamine-xylazine (K, 100 mg/kg; X, 10 mg/kg) and ketamine-dexmedetomidine (K, 75 mg/kg; D, 1.0 mg/kg) for their ability to produce anesthesia, their tissue tolerance, and the reversibility of their effects by atipamezole (1.0 mg/kg) after intraperitoneal administration to Wistar Han rats. Both anesthetic combinations led to a comparable level of anesthesia over a 30-min period. However, the administration of KD led to a 20% decrease in heart rate, 33% decrease in respiratory rate, and a 20% decrease in peripheral oxygen saturation from baseline levels. Intraperitoneal administration of saline and both anesthetic combinations was associated with mild transient increases in serum ALT and AST concentrations in the absence of histomorphologic findings in liver. Muscle and tissue necrosis at the intraperitoneal injection sites correlated with increases in serum creatine kinase concentrations in rats given KD or KX; these increases were more severe in the KX group than the KD group. Compared with KX, intraperitoneal administration of KD offered better local tolerance and anesthesia of similar quality and depth.