This study investigated the impact of heart failure with a preserved ejection fraction (HFpEF) on neuromuscular fatigue and peripheral hemodynamics during small muscle mass exercise not limited by cardiac output. Eight HFpEF patients (ejection-fraction: 61±2%, NYHA II-III) and eight healthy-controls performed dynamic single-leg knee-extension exercise [80% peak workload] to task-failure and maximal intermittent isometric quadriceps contractions (8×15-s, 20-s rest). Controls repeated knee-extension at the same absolute workload as the HFpEF. During knee-extension, leg blood flow was quantified using Doppler ultrasound. Pre- to post-exercise changes in quadriceps twitch-torque (ΔQtw, peripheral fatigue), voluntary-activation (ΔVA, central fatigue), and corticospinal excitability were quantified. At the same relative intensity, HFpEF (24±5W) and controls (42±6W) had a similar time to task-failure (~10min), ΔQtw (~50%), and ΔVA (~6%) (P>0.3). This resulted in a greater exercise-induced change in neuromuscular function per unit work in HFpEF, which was significantly correlated with a slower leg blood flow response time (r=0.77). Knee-extension exercise at the same absolute workload resulted in a ~40% lower leg blood flow and greater ΔQtw (56±15 vs 11±10%) and ΔVA (5±3 vs 0±2%) in HFpEF than controls (P<0.05). Corticospinal excitability remained unaltered during exercise in both groups. Finally, despite a similar ΔVA, ΔQtw was larger in HFpEF compared to controls during isometric exercise (-49±9 vs -23±2%, P<0.05). In conclusion, HFpEF are characterized by a greater susceptibility to neuromuscular fatigue during exercise not limited by cardiac output. The patients' compromised peripheral hemodynamic response to exercise likely accounts, at least partly, for the attenuated fatigue resistance in this population.