Background: Previous data have pointed to the fact that vascular function is significantly impaired in patients with end-stage renal disease (ESRD). We aimed to better characterise vasodilation and exercise capacity in both ESRD and chronic heart failure (CHF) patients. Methods: A total of 30 ESRD patients (23 male; mean age 45.7 ± 9.9 years) were included in a prospective proof-of-concept study at a tertiary care academic centre. The patients underwent forearm venous plethysmography with post-ischaemic peak blood flow (PF) and flow-dependent flow (FDF) testing as well as cardiopulmonary exercise testing during the morning of the day following the last haemodialysis. After matching for age, gender, and body mass index, the data were compared to 30 patients with CHF and 20 age-matched healthy controls. Results: PF in ESRD patients was reduced when compared to that in CHF patients (12.5 ± 4.2 vs. 15.6 ± 6.9 ml/100 ml/min; p = 0.048) and healthy controls (26.4 ± 9.3 ml/100 ml/min; p < 0.001). When compared to controls, FDF was significantly reduced in ESRD patients (7.6 ± 3.1 vs. 6.0 ± 2.5 ml/100 ml/min; p = 0.03), but not in CHF patients, whereas resting blood flow did not differ between the ESRD, CHF, and healthy control groups. In contrast to indices of vasodilative capacity, maximum exercise capacity (peakVO2) was higher in ESRD when compared to CHF patients (23.8 ± 7.3 vs. 18.8 ± 5.2 ml/min/kg), but significantly impaired when compared to controls (32.8 ± 6.7 ml/min/kg; p < 0.001). Conclusion: In this proof-of-concept study, exercise capacity was relatively preserved, while vasodilative capacity was substantially impaired in ESRD patients. Additional studies are warranted to examine the underlying mechanisms and potential clinical implications of our findings.