BACKGROUND In flammation plays a fundamental role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In most patients, in flammation develops secondary to cardiometabolic comorbidities, some, HFpEF develops in the setting of an underlying systemic in flammatory disease such as rheumatoid arthritis systemic lupus erythematosus. OBJECTIVES This study aimed to investigate the prevalence, pathophysiology, and outcome of patients with HFpEF and autoimmune or primary in flammatory disorders. METHODS Of 982 consecutively evaluated patients with HFpEF diagnosed, 79 (8.0%) had autoimmune disorders. HFpEF was de fined by invasive cardiopulmonary hemodynamic exercise testing. RESULTS Female sex, higher heart rate, lower hemoglobin, absence of atrial fibrillation, and absence of coronary artery disease were independently associated with autoimmune disorders. Hemodynamics at rest and exercise did not differ between the groups, but peripheral oxygen extraction was lower in those with autoimmune disorders, re flected by lower arterial -venous oxygen content difference at rest (4.2 +/- 0.7 mL/dL vs 4.6 +/- 1.0 mL/dL; P < and during exercise (9.3 +/- 2.2 mL/dL vs 10.4 +/- 2.2 mL/dL; P < 0.001), suggesting a greater peripheral de ficit, ventilatory ef ficiency (VE/VC O-2 slope, regression slope relating minute ventilation to carbon dioxide output) was more impaired (38.0 +/- 7.9 vs 36.2 +/- 7.3; P = 0.043). Patients with autoimmune disorders had a higher risk of death heart failure (HF) hospitalization compared with those without in adjusted analyses (HR: 1.95 [95% CI: 1.17-3.27]; P = 0.011) over a median follow-up of 3.0 years, which was primarily attributable to higher risk of HF hospitalization (HR: 2.87 [95% CI: 1.09-7.57]; P = 0.033). CONCLUSIONS Patients with HFpEF and autoimmune disorders have similar hemodynamic derangements but greater peripheral de ficits in oxygen transport and higher risk for adverse outcome compared with those without. (J Am Coll Cardiol HF 2024;12:1257 -1269) (c) 2024 by the American College of Cardiology Foundation.