Refinements in extracorporeal membrane oxygenation (ECMO) equipment, including heparin-coated surfaces, centrifugal pump, membrane oxygenator, and more biocompatible pump-oxygenator circuits, have reduced procedure-related complications and have made ECMO a safe and effective therapy for critical patients. The aim of this study was to evaluate the performance of two different ECMO circuit systems in a clinical setting and compare their outcomes. From December 2004 to December 2009, 121 patients required ECMO for primary or postcardiotomy cardiogenic shock at our heart center. We used the Medtronic circuit system in our earlier series (Group M, n = 64), and from July 2007, ECMO was carried out mainly with the Quadrox D PLS circuit system (Group Q, n = 56). We retrospectively summarized and analyzed the data of these patients. The evaluation was based on the comparison between properties of the membrane oxygenators and pumps, anticoagulation therapy, circuit-related complications, and clinical outcomes. Support pump flow rates, platelet counts, and trans-membrane pressure drops (TMPDs) of preoxygenator and postoxygenator pressures were compared between two groups at the time of support established (T1) and support established for 24 h (T2). There were no significant differences between the two groups with regard to patient characteristics and pre-ECMO data. The support pump flow rates and platelet counts at different times were comparable in the two groups. The cannulation technique, ECMO duration, and mean heparin dosage were similar in both groups. There were also no significant differences between the groups in mortality or complications related to bleeding and organ dysfunction. Compared with the M group, the Q group experienced less mechanical failure of the ECMO circuit. The Quadrox PLS circuit system showed less circuit thrombus formation (P < 0.045), less plasma leakage (P < 0.001), and less need for replacement of oxygenators (P < 0.001). Furthermore, frequency of hemolysis during ECMO was significantly lower (P < 0.045). In addition, at T1 and T2, TMPDs were significantly lower in the Q group. Our results suggest that both ECMO circuit systems provide similar effects for safe clinical application, but the Quadrox PLS ECMO circuit system demonstrated partially improved biocompatibility in terms of improved cell preservation, lower TMPDs, less plasma leakage, and thrombus formation.