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Background and Objectives: Preoperative red blood cell (RBC) transfusions increase post-operative venous thromboembolic (VTE) events. Erythropoietin-stimulating agents (ESAs) increase VTE risk in cancer patients; we aimed to assess ESA versus RBC-associated VTE risks in a broad population of surgical patients., Materials and Methods: We queried TriNetX Diamond Network from 2006 to 2023, comparing patients with anaemia within 3 months preoperatively who received preoperative ESAs with or without intravenous (IV) iron to patients who received preoperative RBCs. Sub-analyses included (1) all surgeries and (2) cardiovascular surgeries. We propensity score matched for demographics, comorbidities, medical services, post-treatment haemoglobin (g/dL) and, for all-surgery comparisons, surgery type. Outcomes included 30-day post-operative mortality, VTE, pulmonary embolism (PE), disseminated intravascular coagulation (DIC) and haemoglobin., Results: In our 19,548-patient cohorts, compared with preoperative RBC transfusion, ESAs without IV iron were associated with lower mortality (relative risk [RR] = 0.51 [95% confidence interval (CI), 0.45-0.59]), VTE (RR = 0.57 [0.50-0.65]) and PE (RR = 0.67 [0.54-0.84]). Post-operative haemoglobin was higher in the ESA without IV iron cohort compared with the transfusion cohort (10.0 ± 1.4 vs. 9.4 ± 1.8 g/dL, p = 0.002). Cardiac surgical patients receiving ESAs with or without IV iron had lower risk for post-operative mortality, VTE and PE (p < 0.001) than those receiving RBCs. Post-operative haemoglobin differed between patients receiving ESAs with IV iron versus RBCs (10.1 ± 1.5 vs. 9.4 ± 1.9 g/dL, p = 0.0009)., Conclusion: Compared with surgical patients who were transfused RBCs, ESA recipients had reduced 30-day post-operative risk of mortality, VTE, PE and DIC and increased haemoglobin levels. IV iron given with ESAs improved mortality., (© 2024 International Society of Blood Transfusion.)