Orthotopic liver transplantation in mice and rats is used to study a wide range of scientific questions. Inhalant anesthesia is widely used in liver transplantation models in rodents, but drawbacks of inhalant anesthetics include issues of cost, safety, and ease of use. The goal here was to find an effective injection anesthesia protocol that would not directly influence metabolic or functional parameters after liver transplantation. We compared intraperitoneal injection of a ketamine-xylazine-acepromazine cocktail (KXA) with isoflurane during 50% liver transplantation in mice and rats. Anesthesia with KXA had rapid induction (5 +/- 3 min) and a long duration of surgical anesthesia (70 +/- 10 min). The 2 methods of anesthesia produced no significant differences in liver injury (histology, serum alanine aminotransferase and total bilirubin concentrations), inflammation (IL6, TNF alpha, myeloperoxidase activity), regeneration (incorporation of 5-bromo-2'-deoxyuridine, mitotic index, restitution of liver weight), or 7-d survival. In conclusion, a KXA regimen is a safe and effective injectable anesthetic for rodent liver transplantation and is a suitable substitute for currently used inhalant anesthesia. Injectable anesthetics offer advantages in terms of cost, personal safety, and ease of use and will be particularly beneficial to microsurgeons during their training period in liver transplantation.