Objective Survival after out-of-hospital cardiac arrest (OHCA) depends on multiple factors, mostly quality of chest compressions. Studies comparing manual compression with a mechanical active compression-depression device (ACD) have yielded controversial results in terms of outcomes and injury. The aim of the present study was to determine whether out-of-hospital ACD cardiopulmonary resuscitation (CPR) use is associated with more skeletal fractures and/or internal injuries than manual compression, with similar duration of cardiopulmonary resuscitation (CPR) between the groups. Methods The cohort included all patients diagnosed with out-of-hospital cardiac arrest (OHCA) at a tertiary medical center between January 2018 and June 2019 who achieved return of spontaneous circulation (ROSC). The primary outcome measure was the incidence of skeletal fractures and/or internal injuries in the two groups. Secondary outcome measures were clinical factors contributing to skeletal fracture/internal injuries and to achievement of ROSC during CPR. Results Of 107 patients enrolled, 45 (42%) were resuscitated with manual chest compression and 62 (58%) with a piston-based ACD device (LUCAS). The duration of chest compression was 46.0 minutes vs. 48.5 minutes, respectively (p=0.82). There were no differences in rates of ROSC (53.2% vs.50.8%, p=0.84), cardiac etiology of OHCA (48.9% vs.43.5%, p=0.3), major complications (ribs/sternum fracture, pneumothorax, hemothorax, lung parenchymal damage, major bleeding), or any complication (20.5% vs.12.1%, p=0.28). On multivariate logistic regression analysis, factors with the highest predictive value for ROSC were cardiac etiology (OR 1.94;CI 2.00–12.94) and female sex (OR 1.94;CI 2.00–12.94). Type of arrhythmia had no significant effect. Use of the LUCAS was not associated with ROSC (OR 0.73;CI 0.34–2.1). Conclusion This is the first study to compare mechanical and manual out-of-hospital chest compression of similar duration to ROSC. The LUCAS did not show added benefit in terms of ROSC rate, and its use did not lead to a higher risk of traumatic injury. ACD devices may be more useful in cases of delayed ambulance response times, or events in remote locations.