Preoperative anemia is a risk factor for postoperative morbidity and in-hospital mortality in cardiac surgery. However, it is not known whether treatment of anemia before cardiac surgery by administering recombinant human erythropoietin (rhEPO) plus iron improves postoperative outcomes and decreases red blood cell transfusions in these patients. In 1998 a collection of consecutive data for patients who underwent valve replacement was initiated and the inclusion criterion was anemia. Treatment with rhEPO was given at a dose of 500 IU/kg/day every week for 4 weeks and the fifth dose 48 hours before valve replacement. During each rhEPO session, patients received intravenous iron sucrose supplementation. The intervention cohort (2006 to 2011) included 75 patients and the observation cohort was composed of 59 patients who did not receive any treatment (1998 to 2005). Multivariable logistic regression analysis showed that administration of combined therapy was independently associated with decreased postoperative morbidity (odds ratio [OR] 0.13, 95% confidence interval [CI] 0.03 to 0.59 p = 0.008) and in-hospital mortality (OR 0.16, 95% CI 0.28 to 0.95 p = 0.04) after adjusting for logistic European System for Cardiac Operative Risk Evaluation score, type of intervention, time of cardiopulmonary bypass, and year of surgery. Individually, this treatment also decreased postoperative renal failure (OR 0.23, 95% CI 0.06 to 0.88, p = 0.03). Rate of red blood cell transfusion decreased from 93% in the observation cohort to 67% in the intervention cohort as did days of hospitalization (median, 15 days, 10 to 27, versus 10 days, 8 to 14, respectively, p = 0.01 for all comparisons). In conclusion, administration of intravenous rhEPO plus iron in anemic patients before valve replacement improves postoperative survival, decreases blood transfusions, and shortens hospitalization. © 2012 Elsevier Inc. All rights reserved.