Background— To assess cardiovascular actions of APJ agonism during prolonged (Pyr 1 )apelin-13 infusion and renin–angiotensin system activation. Methods and Results— Forty-eight volunteers and 12 patients with chronic stable heart failure attended a series of randomized placebo–controlled studies. Forearm blood flow, cardiac index, left ventricular dimensions, and mean arterial pressure were measured using bilateral venous occlusion plethysmography, bioimpedance cardiography, transthoracic echocardiography, and sphygmomanometry, respectively, during brief local (0.3–3.0 nmol/min) and systemic (30–300 nmol/min) or prolonged systemic (30 nmol/min) (Pyr 1 )apelin-13 infusions in the presence or absence of renin–angiotensin system activation with sodium depletion or angiotensin II coinfusion. During sodium depletion and angiotensin II coinfusion, (Pyr 1 )apelin-13–induced vasodilatation was preserved ( P <0.02 for both). Systemic intravenous (Pyr 1 )apelin-13 infusion increased cardiac index, whereas reducing mean arterial pressure and peripheral vascular resistance index ( P <0.001 for all) irrespective of sodium depletion or angiotensin II (0.5 ng/kg per minute) coinfusion ( P >0.05 for all). Prolonged 6-hour (Pyr 1 )apelin-13 infusion caused a sustained increase in cardiac index with increased left ventricular ejection fraction in patients with chronic heart failure (ANOVA; P <0.001 for all). Conclusions— APJ agonism has sustained cardiovascular effects that are preserved in the presence of renin–angiotensin system activation or heart failure. APJ agonism may hold major promise to complement current optimal medical therapy in patients with chronic heart failure. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00901719, NCT00901888, NCT01049646, NCT01179061.