We sought to investigate the impact of multivessel disease (MVD) with and without a chronic total occlusion (CTO) in a non-infarct-related artery (IRA) on mortality in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). In the HORIZONS-AMI trial, of 3283 patients undergoing primary PCI, 1524 patients (46.4%) had single-vessel disease (SVD), 1477 (45.0%) had MVD without a CTO, and 283 (8.6%) had MVD with a CTO in a non-IRA. Compared with SVD patients and MVD patients without a CTO, patients with a non-IRA CTO were significantly less likely to achieve post-procedural TIMI 3 flow (P = 0.0003), more often had absent myocardial blush (P = 0.0002), and less frequently achieved complete ST-segment resolution (P = 0.0001). By multivariable analysis, MVD with CTO in a non-IRA was an independent predictor of both 0- to 30-day mortality [hazard ratio (HR) 2.88, 95% confidence interval (CI) 1.41–5.88, P = 0.004] and 30-day to 3-year mortality (HR 1.98, 95% CI 1.19–3.29, P= 0.009), while MVD without a CTO was a significant predictor for 0- to 30-day mortality (HR 2.20, 95% CI 1.00–3.06, P = 0.049) but not late mortality. In patients with STEMI undergoing primary PCI in the HORIZONS-AMI trial, MVD with or without a CTO in a non-IRA was an independent predictor of early mortality. The presence of a CTO in a non-IRA was also an independent predictor of increased late mortality to 3 years.