Objective: Closed circuit extracorporeal circulation (CCECC) has been developed to reduce deleterious effects of standard cardiopulmonary bypass (CPB). This study compares the effects of CCECC (CORx system), CPB, and off-pump coronary artery bypass grafting (OPCAB) on red blood cell damage, coagulation activation, fibrinolysis and cytokine expression. Methods: Thirty patients underwent coronary artery bypass grafting (CABG). Twenty of them were randomized into two groups: CCECC (n=10), CPB (n=10). While not randomized, OPCAB (n=10) served as a separate reference group. CCECC and CPB patients received cardioplegic arrest. Interleukin 6 (IL-6), free hemoglobin (fHb), von Willebrand factor activity (vWf), thrombin–antithrombin-III-complex (TATc), prothrombin fragment 1.2 (F 1+2) and plasmin–antiplasmin complex (PAPc) were assessed preoperatively, perioperatively and 24h postoperatively. Results: CCECC showed significantly lower red blood cell damage than CPB (fHb: CCECC, 7.1± 5.7μmol/l; CPB, 16.8±11.4μmol/l; P=0.025; OPCAB, 3.4±1.1μmol/l). Perioperatively, CCECC exhibited significantly lower activation of coagulation and fibrinolysis than CPB, but did not differ from OPCAB (vWf: CCECC, 133±52%; CPB, 241±128%; P=0.052; OPCAB, 153±58%; TATc: CCECC, 4.7±0.9ng/ml; CPB, 31.1±15.8ng/ml; P≪0.001; OPCAB, 2.4±0.6ng/ml; PAPc: CCECC, 214±30ng/ml; CPB, 897±367ng/ml; P≪0.001; OPCAB, 253±98ng/ml). In contrast, fibrinolysis markers and IL-6 were markedly increased in CCECC postoperatively (PAPc: CCECC, 458±98ng/ml; CPB, 159±128ng/ml; P≪0.001; OPCAB, 262±174ng/ml; IL-6: CCECC, 123.4±49.8pg/dl; CPB, 18.8±13.1pg/dl; P≪0.001; OPCAB, 31.6±26.2pg/dl). Conclusions: CCECC for CABG is associated with a significant reduction of red blood cell damage and activation of coagulation cascades similar to OPCAB when compared with conventional CPB while a delayed fibrinolytic and inflammatory activity was observed. These findings require further investigation to verify the promising concept of CCECC.