Introduction: Excessive volume unloading of the left ventricle (LV) affects the right ventricular (RV) function by causing shift of the ventricular septum during left ventricular assist device (LVAD) support in patients with mitral regurgitation (MR). Optimal settings of LVAD that control MR without RV dysfunction are required. We developed a novel cardiac-cycle synchronized rotational speed (RS) modulation system for a continuous-flow LVAD and assessed the system in a goat model of MR. Methods: We implanted EVAHEART (Sun Medical Technology Research Corp.) through left thoracotomy in six adult goats weighing 66.4 ± 10.7 kg. After implantation of the device, severe MR was induced with inflation of a temporary inferior vena cava filter that was placed in the mitral valve. The severity of MR was defined by left ventriculography and echocardiography. We evaluated total flow (TF: the sum of aortic flow and pump flow), RV fractional area change (RVFAC) calculated by echocardiography, left atrial pressure (LAP), LV end-diastolic pressure (LVEDP), LV end-diastolic volume (LVEDV), and LV stroke work (LVSW) with a bypass rate (pump flow divided by TF) of 100% under four conditions: circuit-clamp, continuous mode, co-pulse mode (increase RS in systole) and counter-pulse mode (increase RS in diastole). Results: TF tended to be higher in counter-pulse mode (3.27 ± 1.09, 3.51 ± 2.14, 3.45 ± 2.58, and 3.75 ± 2.39 L/min, in circuit-clamp, continuous mode, co-pulse mode, and counter-pulse mode, respectively; p > 0.05). RVFAC was significantly higher in counter-pulse mode than in co-pulse mode (0.68 ± 0.05 vs 0.51 ± 0.08 , p < 0.05). LAP was significantly lower in all the driving modes than in circuit-clamp. LVEDP, LVEDV and LVSW, shown as percentages of those in circuit-clamp (= 100%), were significantly lower in counter-pulse mode than in circuit-clamp (54.43 ± 32.05, 89.6 0 ± 4.23, and 60.30 ± 28.41 %, respectively; p < 0.05). Conclusions: Good control of MR in counter-pulse mode could be achieved with enough LV volume unloading during diastole not to leave blood that regurgitates during systole. Given higher TF and RVFAC in counter-pulse mode, the mode has less adverse effects on the RV function. In conclusion, the mode may offer a favorable control of MR with minimizing RV dysfunction.