Patients presenting for cardiac surgery with cardiopulmonary bypass (CPB) are more likely to have pre-existing comorbidities, which has resulted in a steady increase in the risk associated with CPB. The resulting challenge has mandated the optimization of perfusion care. The purpose of this study was to retrospectively evaluate the impact of a number of simultaneous, evidence based perfusion care changes on patient outcome. After Institutional Review Board approval, two groups of patients were compared. The control group (n = 317) included all patients undergoing CPB in a 12-month period preceding a multifaceted change in perfusion techniques. The treatment group (n = 259) included all patients undergoing CPB in the 12-month period after the changes, which included the incorporation of updated continuous blood gas monitoring, biocompatible circuitry, updated centrifugal blood propulsion, continuous autotransfusion technology, new generation myocardial protection instrumentation, plasmapheresis, topical platelet gel application, excluding hetastarch while increasing the use of albumin, viscoelastographic coagulation monitoring, and implementing a quantitative quality improvement program. After univariate analysis, propensity scoring and multiple conditional logistical regression were used to control for demographic, preoperative, operative, and postoperative parameters. Results of the primary endpoints revealed a lower mortality rate in the treatment group (4% vs. 9% [95% confidence interval 1.33, 7.72], p = 0.009), lower transfusion rate (51% vs. 59% [1.00, 2.11], p = 0.048), and lower complication rate (55% vs. 65% [1.06,2.19], p = 0.025) despite having similar predicted mortality (11 [2,22] vs. 11[3,22], p = NS) and other preoperative and operative parameters. The lower mortality rate was concurrent with a trend towards a lower incidence of complications, consistent with the differences in primary outcomes. In conclusion, the patients treated after the implementation of a multifactorial improvement plan using evidence based changes in CPB care had decreased complication and mortality rates.