Background: For patients hospitalized with heart failure (HF) who are inadequately responsive to medical therapy, the options include ventricular assist devices and cardiac transplant. In animal models and patients, continuous aortic flow augmentation using the Orqis Medical Cancion System (Orqis Medical Corporation, Lake Forest, California), a percutaneously placed arterial-to-arterial circuit (continuous flow up to 1.5 L/min) with an extracorporeal, magnetic, centrifugal pump, improves hemodynamics and renal function with benefits persisting 24 hours after discontinuation. Methods and Results: The Multi-center Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy is enrolling patients hospitalized with HF who are randomized to continuous aortic flow augmentation or medical therapy alone. Entry requires persistent HF, elevated pulmonary capillary wedge pressure, reduced cardiac index, and impaired renal function or substantial diuretic requirement despite intravenous inotrope or vasodilator treatment. The primary efficacy end point is a composite including the components of 72- to 96-hour pulmonary capillary wedge pressure reduction and days alive out of hospital with no mechanical support for more than 35 days. Additional end points include changes in serum creatinine, N-terminal pro-B-type natriuretic peptide, and health-related quality of life. Conclusions: The Multi-center Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy tests the hypothesis that continuous aortic flow augmentation improves the clinical status and outcomes in patients hospitalized with HF exacerbation who are inadequately responsive to medical therapy. © 2007 Elsevier Inc. All rights reserved.