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Background: Successful translation of pre-clinical treatment strategies into clinical therapies depends on reproducible, conclusive models. To date, two distinctive procedures for the induction of myocardial ischemia-reperfusion to test novel therapies for myocardial infarction (MI) are commonly used. The first method applies coronary artery ligation via an open chest procedure, requiring invasive surgery. Alternatively, the coronary artery is occluded by balloon inflation via a transluminal, minimally invasive procedure. In the current study we hypothesized that invasive surgery as for open chest procedures reduces myocardial infarct size and preserves cardiac function post-MI. Methods: Pigs (n=14) were subjected to 75-minute balloon occlusion followed by 3 days of reperfusion. In 7 pigs, the balloon occlusion was preceded by medial sternotomy (MS) that is normally performed for open chest coronary artery ligation. In the remaining 7 pigs the same procedure was performed without sternotomy (NS). Cardiac damage was determined by histological infarct size, 3D-echocardiography and troponin I measurements. The area at risk (AAR) was assessed through Evans blue injection. Circulating leukocyte numbers were measured at baseline, ischemia and reperfusion. Results: Heart rate and blood pressure did not differ significantly between the two groups during the procedure. Also the area at risk (AAR) was comparable between groups (19.8±1.6% (NS) vs. 19.7±3.4% (MS), p=ns). We observed a significantly smaller infarct size as a percentage of the AAR in pigs subjected to sternotomy (67.6±10.2% (NS) vs. 49.3±14.8% (MS), p=0.024), culminating in a significantly higher left ventricular ejection fraction (39.5±3.8% (NS) vs. 47.9±7.1% (MS), p=0.022). Furthermore, troponin I levels 1 hour after reperfusion were significantly different between the two groups (127.6±100.4 ng/mL (NS) vs. 24.5±13.1 (MS) ng/mL, p=0.030). Leukocyte count after 30 minutes of reperfusion was higher in the MS group than the NS group (14.5±3.1*106 cell/mL (NS) vs. 19.0±3.0*106 cell/mL (MS); p=0.023). Conclusion: Invasive surgery required for an open chest temporary coronary artery ligation reduces infarct size compared to minimally invasive surgery in a porcine model of myocardial infarction, despite increased leukocyte numbers. This confounding effect should be taken into account when assessing therapeutic efficacy for novel treatment strategies to treat myocardial infarction.