Background The early assessment of heart failure (HF) risk in patients with acute coronary syndrome (ACS) can help reduce mortality. S100A8/A9 is not only rapidly released after myocardial ischemia, but is also involved in reperfusion injury, which is an important predictor of HF after ACS. We attempted to construct a reliable HF risk stratification tool for evaluating patients with ACS after reperfusion therapy based on S100A8/A9 dynamic changes. Methods and Results This prospective study included 3 independent cohorts of patients with ACS who received reperfusion therapy. The discovery cohort was divided into 2 subgroups: the longitudinal subgroup (n=264) with serum S100A8/A9 levels measured at admission and on days 1, 2, 3, and 4 postadmission, respectively, and the 2‐point subgroup (n=798) with S100A8/A9 levels measured at admission and on day 1 postadmission, respectively. Validation cohorts 1 (n=1399) and 2 (n=1183) both had S100A8/A9 levels measured on day 1 postadmission. HF events included in‐hospital HF events after the initial presentation and long‐term HF events after discharge. The median follow‐up for the discovery cohort, validation cohort 1, and validation cohort 2 was 4.2, 2.6, and 1.8 years, respectively. In the discovery cohort, S100A8/A9's predictive ability at day 1 surpassed other time points. Through the S100A8/A9‐guided risk stratification, patients deemed high risk (>7900 ng/mL) exhibited a higher 1‐year HF event rate (46% versus 2%, 38% versus 5%) than patients at low risk (