An extracorporeal life support system (ECLS) with a conventional membrane oxygenator requires a driving force for the blood to pass through hollow fiber membranes. We hypothesized that if a gravity-flow hollow fiber membrane oxygenator is installed in the circuit, the twin blood sacs of a pulsatile ECLS (the Twin-Pulse Life Support, T-PLS) can be placed downstream of the membrane oxygenator. This would increase pump output by doubling pulse rate at a given pumpsetting rate while maintaining effective pulsatility. The purpose of this study was to determine the optimal circuit configuration for T-PLS with respect to energy and pump output. Animals were randomly assigned to 2 groups in a total cardiopulmonary bypass model. In the serial group, a conventional membrane oxygenator was located between the twin blood sacs of the T-PLS. In the parallel group, the twin blood sacs were placed downstream of the gravity-flow membrane oxygenator. Energy equivalent pressure (EEP), surplus hemodynamic energy (SHE) and pump output were collected at the different pump-setting rates of 30, 40, and 50 beats per minute (BPM). At a given pump-setting rate the pulse rate doubled in the parallel group. Percent changes of mean arterial pressure to EEP were 13.0 +/- 1.7, 12.0 +/- 1.9, and 7.6 +/- 0.9% in the parallel group, while 22.5 +/- 2.4, 23.2 +/- 1.9, and 21.8 +/- 1.4 in the serial group at 30, 40, and 50 BPM of pump-setting rates. SHE at each pump setting rate was 20,131 +/- 1408, 21,739 +/- 2470, and 15,048 +/- 2108 erg/ cm3 in the parallel group, while 33,968 +/- 3001, 38,232 +/- 3281, 37,964 +/- 2693 erg/cm3 in the serial group. Pump output was higher in the parallel circuit at 40, and 50 BPM pump-setting rates (3.1 +/- 0.2, 3.7 +/- 0.2 L/min vs. 2.2 +/- 0.1 and 2.5 +/- 0.1 L/min, respectively, p =0.01). Either parallel or serial circuit configuration of T-PLS generates effective pulsatility. As for the pump out, the parallel circuit configuration provides higher flow than the serial circuit configuration by doubling the pulse rate at a given pump-setting rate.