OBJECTIVE: The primary purpose of this study was to compare the percentage of return of spontaneous circulation of in-flight cardiac arrest (IFCA) patients on admission to the emergency department (ED) who received in-flight standard cardiopulmonary resuscitation (s-CPR) versus automated cardiopulmonary resuscitation (a-CPR). SETTING: EMS helicopter (HEMS) service in Midwest USA. METHODS: This was a prospective, consecutive case series of adult patients who had IFCA of any cause managed with a-CPR between October 1, 2012, and February 8, 2016 (40 months), at a helicopter emergency medical service (HEMS) in the Midwestern United States. The series was compared with a historical control of patients who had IFCA managed by s-CPR between June 1, 2009, and September 30, 2012 (40 months). RESULTS: Ninety-five runs (39 s-CPR and 54 a-CPR) were included. There was no significant difference in survival between the 2 groups upon HEMS leaving the ED. Cardiopulmonary resuscitation was performed for a significantly longer period of time in the a-CPR cohort than in the s-CPR cohort, and a significantly higher percentage of patients were undergoing active compressions upon loading into the aircraft in the a-CPR cohort. CONCLUSION: There was no difference in return of spontaneous circulation on ED admission between the 2 compression methodologies. In-flight use of a-CPR allows HEMS providers to be safe and compliant with Federal Aviation Administration regulations. It also meets the public and medical profession's expectations of the treatment of IFCA with high-quality cardiopulmonary resuscitation by HEMS.