© 2014 American Heart Association, Inc. Background-No treatment strategies have been demonstrated to be beneficial for the population for patients with heart failure (HF) and preserved ejection fraction (EF). Methods and Results-The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial was a prospective, single-blinded, randomized controlled clinical trial testing the hypothesis that hemodynamically guided HF management decreases decompensation leading to hospitalization. Of the 550 patients enrolled in the study, 119 had left ventricular EF ≥40% (average, 50.6%), 430 patients had low left ventricular EF (<40%; average, 23.3%), and 1 patient had no documented left ventricular EF. A microelectromechanical system pressure sensor was permanently implanted in all participants during right heart catheterization. After implant, subjects were randomly assigned in single-blind fashion to a treatment group in whom daily uploaded pressures were used in a treatment strategy for HF management or to a control group in whom standard HF management included weight-monitoring, and pressures were uploaded but not available for investigator use. The primary efficacy end point of HF hospitalization rate >6 months for preserved EF patients was 46% lower in the treatment group compared with control (incidence rate ratio, 0.54; 95% confidence interval, 0.38-0.70; P<0.0001). After an average of 17.6 months of blinded follow-up, the hospitalization rate was 50% lower (incidence rate ratio, 0.50; 95% confidence interval, 0.35-0.70; P<0.0001). In response to pulmonary artery pressure information, more changes in diuretic and vasodilator therapies were made in the treatment group. Conclusions-Hemodynamically guided management of patients with HF with preserved EF reduced decompensation leading to hospitalization compared with standard HF management strategies. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00531661.