Safe and effective immobilization of grizzly bears (Ursus arctos) is essential for research and management. Fast induction of anesthesia, maintenance of healthy vital rates, and predictable recoveries are priorities. From September 2010 to May 2012, we investigated these attributes in captive and wild grizzly bears anesthetized with a combination of a reversible α2 agonist (dexmedetomidine [dexM], the dextrorotatory enantiomer of medetomidine) and a nonreversible N-methyl-d-aspartate (NMDA) agonist and tranquilizer (tiletamine and zolazepam [TZ], respectively). A smaller-than-expected dose of the combination (1.23 mg tiletamine, 1.23 mg zolazepam, and 6.04 µg dexmedetomidine per kg bear) produced reliable, fast ataxia (3.7±0.5 min, x̄±SE) and workable anesthesia (8.1±0.6 min) in captive adult grizzly bears. For wild bears darted from a helicopter, a dose of 2.06 mg tiletamine, 2.06 mg zolazepam, and 10.1 µg dexmedetomidine/kg produced ataxia in 2.5±0.3 min and anesthesia in 5.5±1.0 min. Contrary to published accounts of bear anesthesia with medetomidine, tiletamine, and zolazepam, this combination did not cause hypoxemia or hypoventilation, although mild bradycardia (<50 beats per min) occurred in most bears during the active season. With captive bears, effective dose rates during hibernation were approximately half those during the active season. The time to first signs of recovery after the initial injection of dexMTZ was influenced by heart rate (P<0.001) and drug dose (P<0.001). Intravenous (IV) injection of the reversal agent, atipamezole, significantly decreased recovery time (i.e., standing on all four feet and reacting to the surrounding environment) relative to intramuscular injection. Recovery times (25±8 min) following IV injections of the recommended dose of atipamezole (10 µg/µg of dexmedetomidine) and half that dose (5 µg/µg) did not differ. However, we recommend use of the full dose based on the appearance of a more complete recovery. Field trials confirmed that the dexMTZ atipamezole protocol is safe, reliable, and predictable when administered to wild grizzly bears, especially during helicopter capture operations.