The Medtronic Resting Heart System (RHS) is a heparin-coated, closed perfusion circuit. Clinical results indicate less haemodilution and reduced complement activation, when compared with a traditional circuit leading to fewer postoperative blood transfusions. We evaluated the potential clinical benefits, including reduced transfusion requirements, when using the RHS compared with conventional cardiopulmonary bypass (cCPB). The study group (n = 330) consisted of patients undergoing isolated coronary artery bypass grafting (CABG) using the RHS system during 2005-2009, matched with a control group (n = 609) including patients operated for isolated CABG during 2002-2009, utilizing cCPB. Significantly fewer patients received peri- and postoperative blood transfusions in the RHS group (25 vs. 37%, P < 0.001; mean 1.0 ± 2.6 vs. mean 1.6 ± 2.9 units of packed red blood cells). The incidence of reoperations due to bleeding was low, RHS 2% (n = 8) vs. cCPB 5% (n = 29), with a trend towards no significant difference between groups (P = 0.079). The duration of mechanical ventilation was shorter (mean 7 ± 16 vs. 9 ± 12 h, P < 0.001) for patients in the RHS group. This study demonstrates that CABG performed with the RHS reduces the incidence and magnitude of allogenic blood transfusion and results in a satisfactory clinical outcome.