Measurement of left ventricular end-diastolic pressure (LVEDP) is readily obtainable in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, the prognostic utility of LVEDP during primary PCI has never been studied. LVEDP was measured in 2,797 patients during primary PCI in the Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. Outcomes were assessed at 30 days and 2 years stratified by medians of LVEDP. Multivariable analysis was performed to determine whether LVEDP was an independent determinate of adverse outcomes. The median (interquartile range) for LVEDP was 18 mm Hg (12 to 24). For patients with LVEDP >18 mm Hg versus those with ≤18 mm Hg, hazard ratios (95% confidence intervals) for death and death or reinfarction at 30 days were 2.00 (1.20 to 3.33, p = 0.007) and 1.84 (1.24 to 2.73, p = 0.002), respectively, and at 2 years were 1.57 (1.12 to 2.21, p = 0.009) and 1.45 (1.14 to 1.85, p = 0.002), respectively. Patients in the highest quartile of LVEDP (≥24 mm Hg) were at the greatest risk of mortality. Only a weak correlation was present between LVEDP and left ventricular ejection fraction (LVEF; R2 = 0.03, p <0.01). By multivariable analysis increased LVEDP was an independent predictor of death or reinfarction at 2 years (hazard ratio 1.20, 95% confidence interval 1.02 to 1.42, p = 0.03) even after adjustment for baseline LVEF. In conclusion, baseline increased LVEDP is an independent predictor of adverse outcomes in patients with STEMI undergoing primary PCI even after adjustment for baseline LVEF. Patients with LVEDP ≥24 mm Hg are at the greatest risk for early and late mortality.