Background: Despite the current drug and device therapies, heart failure remains associated with high rates of disability, morbidity, and mortality. There is a need for newer therapies. One investigational approach is the use of ventricular support devices. These devices reduce ventricular wall stress leading to decreases in left ventricular (LV) volumes, dimensions, and mass. Ventricular support devices have been shown to reverse pathological ventricular remodeling, improve systolic function, and improve symptoms of heart failure. The Prospective Evaluation of Elastic Restraint to LESSen the effects of Heart Failure (PEERLESS-HF) trial was designed to further evaluate the safety and efficacy of one such device, the HeartNet (Paracor Medical, Sunnyvale, CA). Methods: The HeartNet is an elastic ventricular restraint device formed from nitinol and covered in silicone, implanted using a minimally invasive approach. The aim of this randomized controlled trial is to compare optimal heart failure drug and device therapy plus the HeartNet (treatment group) to optimal drug and device therapy alone (control group) in patients with advanced systolic heart failure (LV ejection fraction ≤35% and LV end diastolic diameter <85 mm). Primary efficacy end points include the change in peak VO2, quality of life score, and 6-minute hall walk distance from baseline to 6 months. The primary safety objective is to demonstrate noninferiority for all-cause mortality at 12 months. Planned enrollment is for 272 patients at approximately 35 centers in North America. Conclusions: The PEERLESS-HF trial will evaluate the safety and efficacy of ventricular elastic support in advanced systolic heart failure, advancing our knowledge of this investigational approach to heart failure therapy.