Objectives: The purpose of this study was to determine the prognostic value of ST-segment resolution after primary percutaneous coronary intervention (pPCI) versus fibrinolysis. Background: Resolution of the ST-segment has been used as a surrogate end point in trials evaluating reperfusion in acute myocardial infarction; however, its prognostic significance may be limited to patients treated with fibrinolysis. Methods: In the DANAMI-2 (DANish trial in Acute Myocardial Infarction-2) substudy, including 1,421 patients, the ST-segment elevation at baseline, pre-intervention, 90 min, and 4 h was assessed. The ST-segment resolution was grouped as follows: 1) complete ≥70%; 2) partial 30% to <70%; and 3) no resolution <30%. End points were 30-day and long-term mortality and reinfarction. Results: The ST-segment resolution at 90 min was more pronounced after pPCI (median 60% vs. 45%, p < 0.0001), and a catch-up phenomenon was observed at 4 h. In the fibrinolysis group, 30-day and long-term mortality rates were significantly higher among patients without ST-segment resolution, whereas reinfarction rates were higher with complete ST-segment resolution. The ST-segment resolution was not associated with the 2 end points in the pPCI group. By multivariate analysis, ST-segment resolution at 4 h was an independent predictor of lower mortality, but higher reinfarction rates among patients receiving fibrinolytic therapy. Conclusions: The ST-segment resolution at 90 min was more complete after pPCI, suggesting better epicardial and microvascular reperfusion, whereas no difference between treatment strategies was seen at 4 h. The ST-segment resolution at 4 h correlated with decreased mortality, but increased reinfarction rates among patients receiving fibrinolytic therapy, whereas no association was seen for patients receiving pPCI. Consequently, 4-h ST-segment resolution remains an important prognosticator after fibrinolysis, but may be overemphasized as a surrogate end point after pPCI.