Abstract Body (Do not enter title and authors here): Background: In heart failure, sympathetic excess and exercise intolerance impair quality of life. In HFrEF, muscle sympathetic nerve activity (MSNA) is augmented at rest and in response to exercise, of which the latter relates inversely to peak oxygen uptake (VO_2peak). Aims: To determine, in HFpEF: 1) if resting MSNA is elevated, independent of its accompanying comorbidities; and 2) if MSNA responses to exercise are also increased and relate inversely to exercise capacity. Methods: In 13 HFpEF patients (70±6 yrs; LVEF: 63±6%; NTproBNP: 658±610 pg/ml), 17 co-morbid controls (CMC; 67±8 yrs), matched for medication and presence of comorbidities, and 18 healthy controls (HC; 65±8 yrs), we measured, in the seated position, heart rate, blood pressure, and MSNA (microneurography) during: i) 7 min baseline; ii) 2 min isometric (IHG; 40% maximal voluntary contraction [MVC]) or rhythmic handgrip (RHG; 50% and 30% MVC) exercise, followed by 2 min post-HG ischemia (PHGI); and iii) 4 min 1-leg cycling (2 min each at mild and moderate intensity). VO_2peak was obtained by open circuit spirometry. Results: Resting MSNA was higher in HFpEF (48±14 bursts/min) vs. CMC (36±9 bursts/min; P=0.02) and HC (34±12 bursts/min; P<0.01). In HFpEF, relative VO_2peak (16±5 ml/kg/min) was lower vs. CMC (25±7 ml/kg/min; P=0.02) and HC (29±9 ml/kg/min; P<0.001). During HG, MSNA responses were similar in magnitude in all groups (P<0.05), resulting in higher absolute values in HFpEF vs. CMC and HC during HG and PHGI at 40% IHG (P<0.05) and HG only at 50% and 30% RHG (P<0.05). During cycling, MSNA decreased during mild (−4±4 bursts/min; P=0.01) and moderate (−8±6 bursts/min; P<0.001) cycling in HC, was unchanged during mild (+1±6 bursts/min; P=0.42) and moderate (+2±8 bursts/min; P=0.28) cycling in CMC, yet increased in HFpEF during both mild (+8±8 bursts/min; P<0.001) and moderate (+9±10 bursts/min; P<0.001) cycling. In HFpEF, the change in MSNA elicited by moderate cycling related inversely to relative VO_2peak (R²=0.51; P<0.01). No such relationship existed in either CMC or HC (P>0.05). Conclusion: In contrast to comorbidity-matched controls, HFpEF patients exhibit augmented MSNA at rest and during exercise. As with HFrEF, the magnitude of such ‘paradoxical’ sympathoexcitation during dynamic exercise related inversely to exercise capacity, observations consistent with the concept of a peripheral neurogenic, vasoconstrictor limit on exercise in all with heart failure, regardless of LVEF.