PurposeMechanical chest compression devices, such as the AutoPulse®, have been developed to overcome problems associated with manual CPR (M-CPR). Animal and human studies have shown that AutoPulse CPR improves hemodynamic parameters over M-CPR. However, human studies conducted in the prehospital setting have conflicting results as to the AutoPulse's efficacy in improving survival. The Circulation Improving Resuscitation Care (CIRC) Trial is designed to evaluate the effectiveness of integrated AutoPulse-CPR (iA-CPR) (i.e., M-CPR followed by AutoPulse®-CPR) in a randomized controlled trial that addresses methodological issues that may have influenced the results of previous studies. MethodsThis paper describes the methodology of the CIRC trial. ResultsUnlike previous trials the CIRC trial studies iA-CPR where emphasis is placed on reducing “hands-off” time. The trial has six unique features: (1) training of all EMS providers in a standardized deployment strategy that reduces hands-off time and continuous monitoring for protocol compliance. (2) A pre-trial simulation study of provider compliance with the trial protocol. (3) Three distinct study phases (in-field training, run-in, and statistical inclusion) to minimize the Hawthorne effect and other biases. (4) Monitoring of the CPR process using either transthoracic impedance or accelerometer data. (5) Randomization at the subject level after the decision to resuscitate is made to reduce selection bias. (6) Use of the Group Sequential Double Triangular Test with sufficient power to determine superiority, inferiority, or equivalence. ConclusionThis unique, large, multicenter study comparing the effectiveness of iA-CPR to M-CPR will contribute to the science of the treatment of out-of-hospital cardiac arrest as well as to the design of future trials.