Introduction: A newly developed minimized extracorporeal circulation (MECC) designed to enhance biocompatibility during on-pump coronary artery bypass grafting (CABG) was clinically evaluated with special emphasis on its neuroprotective effects. The system is a closed, heparin-coated circuit consisting of only a centrifugal pump and a high performance membrane oxygenator, thus eliminating blood-air contact and thereby reducing typical side effects (inflammation, hemolysis, hemodilution). Methods: 517 patients (159 females, 66 ± 10 years) undergoing CABG with MECC were clinically followed and compared to a matched cohort of 517 patients (144 females, 65 ± 9 years) in whom a conventional open system (CECC) was used. In a prospective-randomized study (MECC n=30; CECC n=30) markers of hemolysis (free plasma haemoglobin, fHb), inflammation (interleukin-6), myocardial (CK-MB, troponin T) and cerebral damage (protein S-100β) were measured. A second prospective-randomized study (MECC n=17; CECC n=18) focused on cerebral tissue oxygenation (HbO2) measured by near-infrared spectroscopy and incidence of gaseous high intensity transient signals (HITS) measured by transcranial doppler. Results: Groups were comparable with respect to preoperative data. Due to the reduced priming volume of the MECC system (450 vs. 1500 ml) patients were less hemodiluted and needed less transfusions (39% vs. 79%). The incidence of typical perioperative complications was significantly reduced in the MECC group (low cardiac output 0.8 vs. 4.3%, atrial fibrillation 12 vs. 33%, ventricular arrhythmias 3.9 vs. 10%, rethoracotomy 0.2 vs. 3.1%, pneumonia 0.8 vs.3.1%, renal insufficiency 0.8 vs. 3.1%, hemodialysis 0.2 vs. 2.2%, stroke 1.0 vs. 3.1%, psychosyndrome 2.6 vs. 7.8%). MECC patients expressed significantly less markers of hemolysis (fHb 21 vs. 208 mg/dl) inflammation (IL-6 830 vs. 1720 pg/l) and organ damage (CK-MB 13.8 vs. 26.1 U/l, TnT 0.03 vs. 0.09 mg/l, S-100β 0.6 vs. 3.8 µg/l). The decline in cerebral tissue oxygenation during extracorporeal perfusion was significantly less severe when MECC instead of CECC was used (HbO2 −3.5 vs. −8.6 mMol). Gaseous microemboli occurred significantly less frequent in the closed minimized compared to the open standard system (HITS 554 vs. 1591). Conclusions: The MECC system offers a safe and adequate perfusion during CABG. Typical side effects of extracorporeal perfusion can be minimized. Neuroprotective potential is documented by better cerebral oxygenation and less microemboli.