Introduction Peak exercise oxygen uptake (pVO2) is significantly worsened when obesity and low hemoglobin (Hb) are present in patients with heart failure and reduced ejection fraction (HFrEF). Iron deficiency (ID) combined with low Hb (ID+Hb) also limits pVO2, but not at the strength initially suspected. The presence of ID+Hb and excess body mass, presumably fat mass and not metabolically active, should further impair pVO2. This study tested the hypothesis that obesity in HFrEF weakens the positive predictive value (PPV) associated with pVO2 in separating patients with ID+Hb from those with normal Hb and no ID (no ID+norm Hb). Methods Treadmill cardiopulmonary exercise testing was performed by 160 HFrEF (overall: 77% men; LVEF 22±8%; BMI 18.5-39.9 kg/m2) (N=50, non-obese ID+Hb; N=40, obese ID+Hb; N=35, non-obese no ID+norm Hb; N=35, obese no ID+norm Hb). BMI was 25±3, 34±3, 26±3, 34±4 kg/m2, respectively. Patients met ESC/HFA criteria for ID: serum ferritin Results Group differences for age, LVEF, and sex were not significant. The pVO2 indexed to body weight for non-obese no ID+norm Hb (19±6 mL/kg/min) was greater (P 0.05). A PPV=92% and AUC=0.77 (P Conclusions For HFrEF with normal Hb and no ID, obesity markedly limits pVO2 to critical levels demonstrated by non-obese patients with ID+Hb. This is an important finding in demonstrating high BMI alone plays a powerful role in impairing pVO2 in HFrEF. Secondary prevention should emphasize weight management therapy for patients with HFrEF.