Modern thrombolytic strategies, including the use of routine invasive evaluation after thrombolytic therapy (TT), may affect the previously documented mortality benefit of primary percutaneous coronary intervention (PPCI) over TT. This study prospectively assessed in-hospital mortality in 5295 unselected patients with ST-segment elevation myocardial infarction treated with PPCI (86%) or with TT (14%) during the period 2007 through 2009 in 73 Belgian hospitals. After adjustment for differences in baseline risk profile, a significant mortality benefit was only present in the high-risk groups: 23.7% for PPCI vs 30.6% for TT. For non–high-risk patients (81% of the study population), the mortality difference was marginal, with in-hospital mortality rates of less than 5% irrespective of reperfusion therapy. Subgroup analysis revealed that mortality benefit of PPCI over early TT (door-to-needle time, <30 minutes) was offset if the door-to-balloon time exceeded 60 minutes.