Safe, effective, and reversible immobilization protocols are essential for the management of free-ranging red wolves (Canis rufus). Combinations using an α₂-adrenoceptor agonist and ketamine have been shown to be effective for immobilization but are not reversible and can produce severe hypertension and prolonged or rough recoveries. To minimize hypertension and provide reversibility, 24 red wolves were immobilized using three medetomidine–butorphanol (MB) combinations without the use of ketamine in the initial injection. All wolves were administered medetomidine (0.04 mg/kg i.m.) and butorphanol (0.4 mg/kg i.m.). Seven wolves received no other immobilization agents (MB wolves), nine received diazepam (0.2 mg/kg i.v.) at the time they were instrumented (MBD wolves), and eight received ketamine (1 mg/kg i.v.) 30 min after instrumentation (MBK30 wolves). Physiologic parameters were monitored during immobilization. The heart rate was similar among the three groups for the first 30 min, and marked bradycardia was noted in one wolf from each group. Hypertension was observed initially in all three groups but was resolved within 10–30 min. The MBK30 wolves had significant elevations in heart rate and transient hypertension after intravenous ketamine administration. Most wolves had mild to moderate metabolic acidemia. Immobilizing drugs were antagonized in all wolves with atipamezole (0.2 mg/kg i.m.) and naloxone (0.02 mg/kg i.m.). The medetomidine-butorphanol-diazepam wolves were also given flumazenil (0.04 mg/kg i.v.). All wolves were standing within 12 min and were fully recovered within 17 min. Medetomamine-butorphanol and MBD combinations provided effective and reversible immobilization of red wolves without the sustained hypertension associated with the use of α₂-adrenoceptor agonist–ketamine combinations. Delaying the administration of ketamine reduced its hypertensive effects.