BACKGROUND High-output heart failure (HF) is an unusual cause of cardiac failure that has not been well-characterized. OBJECTIVES This study sought to characterize the etiologies, pathophysiology, clinical and hemodynamic characteristics, and outcomes of high-output HF in the modern era. METHODS We performed a retrospective analysis of all consecutive patients referred to the Mayo Clinic catheterization laboratory for hemodynamic assessment between 2000 and 2014. Subjects with definite HF, as defined by the Framingham criteria, were compared to controls of similar age and sex. RESULTS The most common etiologies of high-output HF (n = 120) were obesity (31%), liver disease (23%), arteriovenous shunts (23%), lung disease (16%), and myeloproliferative disorders (8%). Compared with controls (n = 24), subjects with high-output HF displayed eccentric left ventricular remodeling, greater natriuretic peptide activation, higher filling pressures, pulmonary hypertension, and increased cardiac output, despite similar ejection fraction. Elevated cardiac output in high-output HF patients was related to both lower arterial afterload (decreased systemic vascular resistance) and higher metabolic rate. Mortality was increased in high-output HF as compared with controls (hazard ratio: 3.4; 95% confidence interval: 1.6 to 7.6). Hemodynamics and outcomes were poorest amongst patients with the lowest systemic vascular resistance. CONCLUSIONS High-output HF is an important cause of clinical HF in the modern era that is related to excessive vasodilation, and most frequently caused by obesity, arteriovenous shunts, and liver disease. Given the high mortality and increasing prevalence of these comorbidities in Western countries, high-output HF must be considered in the differential diagnosis of patients presenting with dyspnea, congestion, and a normal ejection fraction.