Introduction: Mechanical devices offer the ability to provide consistent fixed-depth chest compressions during CPR. Although compression depth is considered a primary determinant of CPR quality, the influence of other device settings has received less attention. Accordingly, we evaluated the combined effect of compression depth and device start position on CPR hemodynamics in a porcine model of cardiac arrest (CA). Methods: Swine (n=119) were subjected to 7-10 min of CA following electrical induction of ventricular fibrillation. CPR was subsequently performed manually (target peak aortic pressure: 100 mmHg; n=73) or with a mechanical compression system (LUCAS 3.1, Stryker; n=46). Within the mechanical CPR group, animals received 102 compressions/min using either factory default settings (“QuickFit” automated suction cup start position; compression depth: 2.1”; n=13) or custom settings (manual suction cup start position; compression depth: 1.8”; n=33). Aortic pressure (Ao), coronary perfusion pressure (CPP), and regional cerebral oxygen saturation (rSO 2 ; via near infrared spectroscopy) were compared between groups after 1 min of CPR. Results: Mechanical CPR with automated suction cup start position and compression depth of 2.1” resulted in significantly higher peak Ao and CPP than mechanical CPR with manual start position and compression depth of 1.8” ( Table ). Compared with manual CPR, only mechanical CPR with automated start position and compression depth of 2.1” led to a higher CPP. However, cerebral rSO 2 values fell from 61±1 % at baseline to 49±1 % during CA (p<0.01) and did not increase during CPR in any group. Conclusion: Compared with a manual start position and compression depth of 1.8”, use of the LUCAS “QuickFit” feature and compression depth of 2.1” led to a significantly higher CPP during mechanical CPR. Future studies are necessary to determine if differences persist during prolonged CPR with and without concomitant vasopressor administration.