BACKGROUND In patients with ST-segment elevation myocardial infarction (STEMI), presentation during off-hours may have an impact on clinical outcomes. Research in this area is not only scarce, but also conflicting. This study investigated the relationship between off-hours presentation and in-hospital clinical outcomes in patients presenting with STEMI. METHODS AND RESULTS We included all consecutive STEMI patients referred to the University of Ottawa Heart Institute as part of a primary percutaneous coronary intervention (PCI) strategy between July 2004 and December 2017 inclusive. Patients were included if they had < 24 hrs of ischemic symptoms and >=1mm ST-segment elevation in two contiguous leads on a 12-lead ECG. Patients who received fibrinolysis or required therapeutic hypothermia were excluded. Patients were stratified into two groups based on the time of presentation at the PCI center: Group 1 consisted of patients presenting during on-hours defined as between 08:00 and 17:59 hrs; Group 2 consisted of patients presenting during the off-hours defined as 18:00 and 07:59 hrs, on weekends, or statutory holidays. The primary outcome was defined as in-hospital mortality. We identified 5626 patients meeting the inclusion criteria: 2150 (38%) in the on-hours group, and 3476 (62%) in the off-hours group. At baseline, the two groups were similar except for lower rates of diabetes (17.6% vs. 20.4%, p=0.01) and smokers (38.2% vs. 41.5%, p=0.02) in the on-hours group. The median door-to-balloon time was 77 min (interquartile range [IQR]: 43-116) in the on-hours group and 102 min (IQR: 76-134) in the off-hours group (p < 0.001), while the median onset-to-door times were no different between the two groups; 95 min (IQR: 58-202) vs 99 min (IQR: 59-208; p=0.5). There were no differences in the rates of stent insertion (91% vs. 90%), balloon-alone PCI (2.9% vs. 2.7%), and coronary bypass surgery (2.9% vs. 2.9%). While the rate of initial TIMI-3 flow in the infarct-related artery was lower in the on-hours group (20% vs. 22.8%, p=0.001), there was no difference between groups in post-catheterization TIMI-3 flow rates (91.8% vs. 91%, p=0.1). In-hospital mortality was lower in the on-hours group (3.4% vs. 4.8%, p=0.03). Cardiogenic shock also occurred less often in the on-hours group (4.8% vs. 6.4%, p=0.02); whereas, there was no difference in stroke (1.1% vs 0.9%, p=0.4) or reinfarction (1.6% vs. 2.5%, p=0.7). CONCLUSION Patients who presented for primary PCI during regular hours had significantly lower in-hospital mortality as compared to patients presenting during off-hours. In patients with ST-segment elevation myocardial infarction (STEMI), presentation during off-hours may have an impact on clinical outcomes. Research in this area is not only scarce, but also conflicting. This study investigated the relationship between off-hours presentation and in-hospital clinical outcomes in patients presenting with STEMI. We included all consecutive STEMI patients referred to the University of Ottawa Heart Institute as part of a primary percutaneous coronary intervention (PCI) strategy between July 2004 and December 2017 inclusive. Patients were included if they had < 24 hrs of ischemic symptoms and >=1mm ST-segment elevation in two contiguous leads on a 12-lead ECG. Patients who received fibrinolysis or required therapeutic hypothermia were excluded. Patients were stratified into two groups based on the time of presentation at the PCI center: Group 1 consisted of patients presenting during on-hours defined as between 08:00 and 17:59 hrs; Group 2 consisted of patients presenting during the off-hours defined as 18:00 and 07:59 hrs, on weekends, or statutory holidays. The primary outcome was defined as in-hospital mortality. We identified 5626 patients meeting the inclusion criteria: 2150 (38%) in the on-hours group, and 3476 (62%) in the off-hours group. At baseline, the two groups were similar except for lower rates of diabetes (17.6% vs. 20.4%, p=0.01) and smokers (38.2% vs. 41.5%, p=0.02) in the on-hours group. The median door-to-balloon time was 77 min (interquartile range [IQR]: 43-116) in the on-hours group and 102 min (IQR: 76-134) in the off-hours group (p < 0.001), while the median onset-to-door times were no different between the two groups; 95 min (IQR: 58-202) vs 99 min (IQR: 59-208; p=0.5). There were no differences in the rates of stent insertion (91% vs. 90%), balloon-alone PCI (2.9% vs. 2.7%), and coronary bypass surgery (2.9% vs. 2.9%). While the rate of initial TIMI-3 flow in the infarct-related artery was lower in the on-hours group (20% vs. 22.8%, p=0.001), there was no difference between groups in post-catheterization TIMI-3 flow rates (91.8% vs. 91%, p=0.1). In-hospital mortality was lower in the on-hours group (3.4% vs. 4.8%, p=0.03). Cardiogenic shock also occurred less often in the on-hours group (4.8% vs. 6.4%, p=0.02); whereas, there was no difference in stroke (1.1% vs 0.9%, p=0.4) or reinfarction (1.6% vs. 2.5%, p=0.7). Patients who presented for primary PCI during regular hours had significantly lower in-hospital mortality as compared to patients presenting during off-hours.