An accurate rhythm analysis during cardiopulmonary resuscitation (CPR) would contribute to increase the survival from out-of-hospital cardiac arrest. Piston-driven mechanical compression devices are frequently used to deliver CPR. The objective of this paper was to design a method to accurately diagnose the rhythm during compressions delivered by a piston-driven device.Data was gathered from 230 out-of-hospital cardiac arrest patients treated with the LUCAS 2 mechanical CPR device. The dataset comprised 201 shockable and 844 nonshockable ECG segments, whereof 270 were asystole (AS) and 574 organized rhythm (OR). A multistage algorithm (MSA) was designed, which included two artifact filters based on a recursive least squares algorithm, a rhythm analysis algorithm from a commercial defibrillator, and an ECG-slope-based rhythm classifier. Data was partitioned randomly and patient-wise into training (60%) and test (40%) for optimization and validation, and statistically meaningful results were obtained repeating the process 500 times.The mean (standard deviation) sensitivity (SE) for shockable rhythms, specificity (SP) for nonshockable rhythms, and the total accuracy of the MSA solution were: 91.7 (6.0), 98.1 (1.1), and 96.9 (0.9), respectively. The SP for AS and OR were 98.0 (1.7) and 98.1 (1.4), respectively.The SE/SP were above the 90%/95% values recommended by the American Heart Association for shockable and nonshockable rhythms other than sinus rhythm, respectively.It is possible to accurately diagnose the rhythm during mechanical chest compressions and the results considerably improve those obtained by previous algorithms.