Abstract Objectives We sought to identify clinical, electrocardiographic (ECG), and angiographic characteristics that are predictive of 3‐year mortality after primary percutaneous coronary intervention (PCI) in patients with non‐anterior ST‐elevation myocardial infarction (NA‐STEMI) from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS‐AMI) trial. Background Which patients with NA‐STEMI undergoing PCI have a poor prognosis is uncertain. Methods NA‐STEMI was defined as ST‐segment elevation in lateral (V5, V6, I, aVL), inferior (II, III, aVF), or inferolateral (I, II, III, aVF, and V5‐V6) ECG leads or posterior myocardial infarction with ST‐segment depression of ≥1 mm in ≥2 contiguous anterior leads. Cox regression was used to identify independent predictors of 3‐year mortality. Missing data were imputed using multiple imputation. Results In HORIZONS‐AMI, 2,578/3,602 patients had no prior coronary artery bypass grafting, underwent single‐vessel PCI, and had baseline ECG data assessed in an independent core laboratory. Among them, 1,495 (58.0%) had NA‐STEMI. Patients with NA‐STEMI had lower 3‐year mortality risk than those with anterior STEMI (4.5% versus 7.1%, P = 0.004). The independent predictors of increased 3‐year mortality in NA‐STEMI were older age (median > 59.0 years), diabetes, reduced LVEF (≤50%), Killip class ≥2, post‐procedure TIMI flow 0–2 versus 3, renal insufficiency, and ST‐resolution <30% at 60 min post‐PCI. Patients with 0, 1, 2, 3, and ≥4 of these risk factors had 3‐year mortality rates of 1.8%, 2.3%, 3.1%, 6.1%, and 36.3%, respectively ( P < 0.0001). Conclusions Although NA‐STEMI carries a better prognosis than anterior STEMI, high‐risk patient cohorts with NA‐STEMI may be identified who have substantial 3‐year mortality.