OBJECTIVE To evaluate with CT the characteristics of brain tissue disruption and skull damage in cadaveric heads of adult horses caused by each of 6 firearm-ammunition combinations applied at a novel anatomic aiming point. SAMPLE 53 equine cadaveric heads. PROCEDURES Heads placed to simulate that of a standing horse were shot with 1 of 6 firearm-ammunition combinations applied at an aiming point along the external sagittal crest of the head where the 2 temporalis muscles form an inverted V. Firearm-ammunition combinations investigated included a .22-caliber long rifle pistol firing a 40-grain, plated lead, solid-core or hollow-point bullet (HPB); a semiautomatic 9-mm pistol firing a 115-grain, jacketed HPB; a semiautomatic .223-caliber carbine firing a 55-grain, jacketed HPB; a semiautomatic .45-caliber automatic Colt pistol firing a 230-grain, jacketed HPB; and a 12-gauge shotgun firing a 1-oz rifled slug. Additional heads placed in a simulated laterally recumbent position were shot with the semiautomatic 9-mm pistol–HPB combination. All heads underwent CT before and after being shot, and images were evaluated for projectile fragmentation, skull fracture, and cerebrum, cerebellum, and brainstem disruption. RESULTS Computed tomography revealed that all firearm-ammunition combinations caused disruption of the cerebrum, cerebellum, and brainstem that appeared sufficient to result in instantaneous death of a live horse. Hollow-point ammunition was as effective as solid-core ammunition with regard to brain tissue disruption. Brain tissue disruption was not affected by head positioning. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the examined firearm-ammunition combinations, when applied at a novel aiming point, appear to be reasonable options for euthanasia of horses.