In this prospective cohort study we addressed the clinical impact of a reduced anticoagulation protocol on the hospital outcome of patients undergoing coronary revascularization with cardiopulmonary bypass. 364 consecutive low to moderate risk patients scheduled for elective isolated coronary operations were admitted to the study. 184 patients (Control Group) received conventional open circuits and full systemic anticoagulation (target activated clotting time 480 seconds); 180 patients (Intraoperative ECMO group) received closed, phosphorylcholine coated circuits and a reduced systemic heparin dose (target activated clotting time 320 seconds). Patients of the Intraoperative ECMO group had less requirement for allogeneic blood products (odds ratio 0.55, 95% confidence interval 0.34-0.92, p = 0.02), a significant containment of blood loss (374 +/- 278 mL vs. 463 +/- 321 mL in Control group, p = 0.005) a lower postoperative peak serum creatinine levels (1.19 +/- 0.48 mg/dL vs. 1.41 +/- 0.94 mg/dL in Control group, p = 0.048), and a significant lower rate of severe morbidity (odds ratio 0.27, 95% confidence interval 0.09-0.81, p = 0.02). A reduction of systemic anticoagulation is feasible with a non-heparin-bonded, closed biocompatible circuit, and results in a significant improvement of the outcome of low to moderate risk coronary patients.