Chemical restraint, whether remote via dart or via hand injection is essential for many veterinary procedures in captive and wild Panthera spp. but carries risk both to the animal and staff involved. Anecdotal patient safety concerns have been raised for the use of Tiletamine-Zolazepam (TZ), particularly in tigers, that have since been disputed. This investigation assesses the incidence of multiple reported anesthetic complications, including ataxia, respiratory depression/apnea, seizures, bradycardia and retching/vomiting, in captive Panthera spp. immobilized with Ketamine-Medetomidine or TZ-Medetomidine. Three hundred and two anesthetic records were provided by Dr. John Lewis with 44% reporting at least one complication (n = 133). Seventeen sedations using ketamine-medetomidine (9.7%) were reported to provide inadequate depth or require top-up ketamine compared to 12.5% (n = 16) in the TZ-medetomidine group. Species, age, reason for immobilization and requirement for maintenance with isoflurane were identified as significant confounding variables within these data. There was no significant difference in the risk of respiratory depression and seizures in tigers immobilized with ketamine-medetomidine or TZ-medetomidine. However, the TZ group were more likely to be ataxic on recovery. There was no significant difference in risk when immobilizing lions with either protocol. Leopards experienced significantly more complications with TZ-medetomidine than ketamine-medetomidine or TZ as a sole agent, suggesting that this is linked to an unknown confounding variable and not the drugs used. In conclusion, this study identified no justification for the contraindication for TZ in the chemical restraint of Panthera spp. including P. tigris.