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Background —Biventricular direct cardiac compression (DCC) has the potential to support the failing heart without the complications associated with a blood/device interface encountered with the use of current ventricular assist devices. A clinically designed DCC device that provides compression pressure around the base of the heart in synchrony with native ventricular contractions was evaluated with the use of an ex vivo and in vivo canine model of heart failure. Methods and Results —The device was tested over a series of ventricular preloads with the use of an ex vivo canine heart preparation and computerized afterload system that mimicked the conditions of heart failure. The end-systolic pressure-volume relation of the left and right ventricles was shifted upward in parallel by DCC, with the magnitude of the shift averaging 40% of the device compression pressure. The device was tested in vivo with the use of a canine model of acute ischemic heart failure in which graded reductions in ventricular function were created through serial coronary artery embolizations. Under the most severe condition of heart failure, DCC improved cardiac output (CO) by 104% (0.80±0.33 to 1.63±0.40 L/min) and mean arterial pressure by 95% (45.6±11 to 89.0±18.2 mm Hg). The CO was typically restored to ≈60% of the normal baseline value, despite attempts to further increase CO by increasing the amount or duration of compression pressure. Conclusions —Nonuniform DCC significantly improves the left and right ventricular pressure-generating capability and, in the setting of acute heart failure, can increase CO and mean arterial pressure. Such DCC devices can potentially avoid the complications associated with currently available ventricular support devices that involve a blood/device interface.