Background Anemia and blood loss occur often in patients with ST‐segment–elevation myocardial infarction (STEMI). In‐hospital hemoglobin drop is associated with 1‐year mortality in patients with acute coronary syndrome. However, data on the effect of hemoglobin reduction on myocardial salvage and long‐term outcomes are scarce. We investigated the impact of in‐hospital hemoglobin drop on myocardial salvage and 5‐year mortality in patients with STEMI treated with primary percutaneous coronary intervention. Methods and Results In‐hospital hemoglobin drop was defined as a decrease in hemoglobin levels from admission and nadir hemoglobin values. Patients were categorized as having the following: no drop, minimal drop (<3 g/dL), minor drop (≥3 to <5 g/dL), and major drop (≥5 g/dL). Myocardial area at risk and infarct size were measured using serial single‐photon emission computerized tomography imaging. The co‐primary outcomes were myocardial salvage and 5‐year all‐cause mortality. Of 1204 patients, 1169 (97.1%) showed a hemoglobin drop during hospitalization: minimal, minor, and major drop occurred in 894 (74.3%), 214 (17.8%), and 61 (5.1%) patients, respectively. Myocardial salvage was reduced in patients with minimal (median, 0.53 [interquartile range, 0.27–0.83]), minor (median, 0.40 [interquartile range, 0.18–0.62]), and major (median, 0.40 [interquartile range, 0.14–0.77]) drop compared with patients without drop (median, 0.70 [interquartile range, 0.44–1.0], P <0.001). After adjusting for covariates, hemoglobin drop remained an independent correlate of poor myocardial salvage. A drop of ≥3 g/dL was associated with reduced left ventricular function at 6 months and with increased mortality at 5‐year follow‐up after STEMI. Conclusions In patients with STEMI undergoing primary percutaneous coronary intervention, in‐hospital hemoglobin drop was associated with reduced myocardial salvage, left ventricular function, and increased long‐term mortality.