OBJECTIVE: Preoperative anemia management reduces red blood cell (RBC) transfusion and adverse outcomes, but how best to optimize the patient's hemoglobin (Hgb) before cardiac surgery remains unclear. The authors sought to determine the optimal treatment of anemia using iron and epoetin alfa before cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Sunnybrook Health Sciences Centre, University of Toronto. PARTICIPANTS: The study comprised 532 consecutive patients referred to the outpatient Blood Conservation Clinic and who underwent cardiac surgery between 2008 and 2018. INTERVENTIONS: Of the 532 patients, 207 received oral iron, 84 received intravenous (IV) iron, 71 received epoetin alfa, 92 received combination therapy, and 78 received no treatment. MEASUREMENTS AND MAIN RESULTS: Multivariate linear, logistic, and Poisson regressions modelled preoperative Hgb, the change from referral to preoperative Hgb (∆Hgb), the odds of transfusion, and the number of RBC units transfused, while accounting for baseline covariates. Higher ∆Hgb was associated with IV iron >600 mg (9.80 g/L [6.17-13.42]), epoetin alfa >80,000 U (5.80 g/L [2.20-9.40]), and higher referral Hgb (1.91 g/L [1.09-2.74] per 10 g/L). Higher preoperative Hgb (odds ratio 0.76 [0.64-0.90]; count ratio 0.84 [0.77-0.93] per 10 g/L) corresponded to a lower likelihood of being transfused and transfusion of fewer RBC units. CONCLUSIONS: Preoperative IV iron >600 mg and epoetin alfa >80,000 U each was associated with significant increases in Hgb. Higher preoperative Hgb was associated with a lower likelihood of transfusion and transfusion of fewer RBC units. The authors recommend that cumulative preoperative doses of IV iron >600 mg and epoetin alfa >80,000 U be used for treatment of anemia before cardiac surgery.