This study aimed to investigate whether Chronic Kidney Disease (CKD) influences O2 supply including O2 delivery and release to the active muscles during maximal physical exercise. Twelve CKD patients undergoing dialysis therapy (HD group) and twelve healthy adults (CTR group) performed an incremental exercise test to determine maximal oxygen uptake (VO2peak). Throughout the exercise, near-infrared spectroscopy allowed the investigation of changes in oxyhemoglobin (∆O2Hb), deoxyhemoglobin (∆HHb), and total hemoglobin (∆THb) in the vastus lateralis muscle. VO2peak was significantly lower in HD group. In addition, HD patients had impaired changes in muscular oxygenation (∆HHb and ∆O2Hb) and blood volume (∆THb) during the exercise (p textless 0.05). Moreover, a positive correlation was observed between VO2peak and muscle blood volume (∆THb) in both groups (p textless 0.05). This study provides the first evidence that HD patients displayed lower VO2peak and blunted muscular deoxyhemoglobin increase during exercise. This result supports the hypothesis of an increase in oxygen affinity and/or mitochondrial dysfunction in this population.