BACKGROUND: Myocardial fibrosis is a key healing response after myocardial infarction driven by activated fibroblasts. Gallium-68-labeled fibroblast activation protein inhibitor ([Ga]-FAPI) is a novel positron-emitting radiotracer that binds activated fibroblasts. OBJECTIVES: The aim of this study was to investigate the intensity, distribution, and time-course of fibroblast activation after acute myocardial infarction. METHODS: A total of 40 patients with acute myocardial infarction underwent hybrid [Ga]FAPI-46 positron emission tomography and cardiac magnetic resonance and were compared with matched control subjects (n = 19) and those with chronic (>2 years) myocardial infarction (n = 20). Intensity of [Ga]FAPI-46 uptake was quantified by maximum target-to-background ratio (TBR). Burdens of fibroblast activation and scar were assessed by percent myocardial involvement of [Ga]FAPI-46 uptake and late gadolinium enhancement, respectively. RESULTS: Myocardial [Ga]FAPI-46 uptake was observed in the acute infarct and peri-infarct regions that exceeded the extent of late gadolinium enhancement (burden 27.8% ± 12.4% vs 15.2% ± 10.6%; P < 0.001). One-third of patients also demonstrated right ventricular involvement. Myocardial [Ga]FAPI-46 uptake was most intense at 1 and 2 weeks before declining at 4 and 12 weeks (TBR 4.0 ± 1.1, 3.7 ± 1.0, 3.1 ± 0.8, and 2.7 ± 0.7; P < 0.001). In comparison with control subjects, increased [Ga]FAPI-46 uptake was observed in chronic (7 ± 6 years ago) infarcts at lower intensity than acute infarction (TBR 1.2 ± 0.1 vs 1.7 ± 0.5 vs 4.0 ± 1.1; P < 0.001). Baseline [Ga]FAPI-46 burden correlated with lower left ventricular ejection fraction (r = -0.606), higher indexed left ventricular end-diastolic volume (r = 0.572), and higher scar burden (r = 0.871) at 1 year (P < 0.001 for all). Increased remote myocardial [Ga]FAPI-46 uptake was associated with left ventricular dilatation and systolic dysfunction. CONCLUSIONS: Myocardial fibroblast activation peaks within a week of acute myocardial infarction and extends beyond the infarct region. It declines slowly with time, persists for years, and is associated with subsequent left ventricular remodeling. (PROFILE-MI-The FAPI Fibrosis Study; NCT05356923).