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Aprotinin is superior to other antifibrinolytic drugs for preventing major blood loss after cardiac surgery but may also increase perioperative mortality. It remains unclear whether its risk-benefit profile differs among low-, moderate-, and high-risk cardiac surgical patients.In this retrospective single-center cohort study, we included 15,365 patients who underwent cardiac surgery with cardiopulmonary bypass from 2000 to 2008. Of these, 1017 received aprotinin (6 × 106 U) and 14,358 received tranexamic acid (50–100 mg/kg). Propensity score methods were used to create a matched-pairs cohort (n = 1544) that adjusted for important between-group differences. The influence of patients' risk status on aprotinin's association with in-hospital mortality, morbidity, and blood loss was measured.In the matched set, aprotinin was only associated with increased acute kidney injury (>50% decrease in estimated glomerular filtration or dialysis; odds ratio 1.5; 95% confidence interval [CI] 1.1–2.1). Patients' risk status significantly influenced the associations of aprotinin with mortality, acute kidney injury, and massive blood loss (transfusion of ≥10 U of red blood cells or need for surgical reexploration). Among high-risk patients, the respective odds ratios were 0.6 (CI 0.3–1.0), 1.1 (CI 0.7–1.7), and 0.7 (CI 0.4–1.04), and among low- to moderate-risk patients, they were 1.5 (CI 0.9–2.7), 2.2 (CI 1.4–3.5), and 1.2 (CI 0.9–1.07) (Breslow-Day test for homogeneity of odds ratios between high-risk versus low- to moderate-risk patients: P < 0.05 for all 3 outcomes).Aprotinin tends to have a better risk-benefit profile than tranexamic acid in high-risk, but not low- to moderate-risk, patients. Its use in high-risk cases may therefore be warranted.