Objective: The combination of electrical phenomena and remote myocardial ischemia is the pathophysiological mechanism of ST segment changes in inferior leads in acute anterior myocardial infarction (MI). We investigated the prognostic value of ST segment changes in inferior derivations in patients with first acute anterior MI treated with primary percutaneous coronary intervention (PCI). Methods: In this prospective single-center analysis, we evaluated the prognostic impact of ST segment changes in inferior derivations on 354 patients with acute anterior MI. Patients were divided into the following 3 groups according to admission ST segment changes in inferior derivations: ST depression (group 1), no ST change (group 2), and ST elevation (group 3). Results: In-hospital multivariate analysis revealed notably high rates of in-hospital death for patients in group 3 compared to patients in group 2 (OR 2.5; 95% CI 1.6-7.6, p < 0.001). Group 1 and group 2 had similar in-hospital and long-term mortality rates. After adjusting for confounding baseline variables, group 3 had higher rates of 18-month mortality (HR 3.3; 95% CI 1.5-8.2, p < 0.001). Conclusion: In patients with a first acute anterior MI treated with primary PCI, ST elevation in inferior leads had significantly worse short-term and long-term outcomes compared to no ST change or ST segment depression.