In this work, we analyzed the prognostic significance of changes in hemoglobin during intensive care unit (ICU) stay in patients with acute coronary syndromes (ACS). We prospectively enrolled 591 patients (62 ± 14 years old, 73% male, 48% ST elevated myocardial infarction) free of blood cell transfusion or bleeding events. Changes in hemoglobin between admission and ICU discharge were obtained. The primary endpoint was death or hospitalization for MI within 6 months. Hemoglobin decreased from 13.65 ± 1.77 to 13.17 ± 1.74 g/dl, p < 0.0001 in the whole population. The end point was reached in 43 patients at a mean follow-up of 180 (range 2–180 days). A decrease in hemoglobin ≥0.9 g/dl (32% of the population) was associated with adverse clinical outcomes (HR 2.37, 95% CI (1.30–4.35), p = 0.005, respectively). In multivariate analysis, age >77 year-old (p = 0.0016), Killip class ≥2 (p = 0.009), anemia (p = 0.0064), decreased estimated glomerular filtration rate (p = 0.003), and hemoglobin decline ≥0.9 g/dl (p < 0.0001) were independently associated with outcome. Hemoglobin decline and anemia both provided additional prognostic information on top of the GRACE score, as demonstrated by a systematic improvement in model global fit, discrimination, and calibration. Hemoglobin decline is frequent during ICU stay in non-bleeding ACS patients. A decline in hemoglobin ≥0.9 g/dl identifies high-risk patients. Identification of these patients refines the prognostic value of the GRACE score.