Ventricular fibrillation (VF) during acute myocardial infarction (AMI) is an important contributor to sudden cardiac death. Large animal models are widely used to study AMI-induced arrhythmia, but the mode of AMI induction ranges from thoracotomy and surgical ligation of a coronary vessel (open-chest) to minimal-invasive techniques, including balloon occlusion (closed-chest). How the choice of induction affects arrhythmia development is unclear. The aim of this study was to compare an open-chest and a closed-chest model with regards to hemodynamics, electrophysiology and arrhythmia development. Forty-two female Danish Landrace pigs (20 open-chest, 22 closed-chest) were anesthetized and occlusion of the mid-left anterior descending coronary artery was performed for 60 min. Opening the chest reduced blood pressure and cardiac output (D -22 mmHg, D -1.5 L/min from baseline, both p<0.001 intra-group). Heart increased with opening of the chest, but increased with balloon placement (p<0.001). AMI-induced ST elevation was lower in the open chest group (p<0.001). Premature ventricular contractions occurred in two distinct phases (0-15 and 15-40 min), the latter of which was delayed in the open-chest group (p=0.005). VF occurred in 7/20 and 12/22 pigs in the open-chest and closed-chest group, respectively (p=0.337), with longer time-to-VF in the open chest group (23.4±1.2 min in open-chest and 17.8±1.4 min in closed-chest; p=0.007). In summary, opening the chest altered hemodynamic parameters and delayed the onset of ventricular arrhythmias. Hence, in the search for mechanisms and novel treatments of AMI-induced arrhythmia, caution should be taken when choosing between or comparing the results from these two models.