Rationale & objective: Previous studies in chronic kidney disease (CKD) showed that vascular dysfunction in different circulatory beds progressively deteriorates with worsening CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with different stages of CKD versus controls. Study design: Observational controlled study. Setting & participants: 90 participants (18 per CKD stage 2, 3a, 3b, 4, and 18 controls). Predictor: CKD stage. Outcomes: Primary, muscle oxygenation at rest; secondary, muscle oxygenation during occlusion-reperfusion and exercise, and muscle microvascular reactivity (hyperemic response). Analytical approach: Continuous measurement of muscle oxygenation [tissue saturation index (TSI%)] using near-infrared-spectroscopy at rest, during occlusion-reperfusion, and during a 3-min handgrip exercise (at 35% of maximal-voluntary-contraction). Aortic pulse-wave-velocity (PWV) and carotid intima-media thickness (cIMT) were also recorded. Results: Resting muscle oxygenation did not differ across the study groups (controls: 64.3±2.9 stage-2: 63.8±4.2 stage-3a: 64.1±4.1 stage-3b: 62.3±3.3 stage-4: 62.7±4.3%; p=0.6). During occlusion, no significant differences among groups were detected in TSIocl magnitude- and occlusion-slope. However, during reperfusion, the TSImax and the hyperemic response were significantly lower in groups of patients with more advanced CKD stages compared to controls (controls: 11.2±3.7 stage-2: 8.3±4.6 stage-3: 7.8±5.5 stage-3b: 7.3±4.4 stage-4: 7.2±3.3; p=0.04). During handgrip exercise, muscle oxygenation (TSIaverage-decline) was marginally lower in patients with CKD than controls, but no significant differences were detected across CKD stages. Limitations: Moderate sample size, cross-sectional evaluation. Conclusions: Although no differences were observed in muscle oxygenation at rest or during occlusion, the microvascular hyperemic response during reperfusion was significantly impaired in CKD and was most prominent in more advanced CKD stages. This impaired ability of microvasculature to respond to stimuli may be a crucial component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance.