This study examined in vivo (1) skeletal muscle oxygenation and microvascular function, at rest and during handgrip exercise, and (2) their association with macrovascular function and exercise blood pressure (BP), in newly diagnosed, never-treated patients with hypertension and normotensive individuals. Ninety-one individuals (51 hypertensives and 40 normotensives) underwent office and 24-hour ambulatory BP, arterial stiffness, and central aortic BP assessment, followed by a 5-minute arterial occlusion and a 3-minute submaximal handgrip exercise. Changes in muscle oxygenated and deoxygenated hemoglobin and tissue oxygen saturation were continuously monitored by near-infrared spectroscopy and beat-by-beat BP by Finapres. Hypertensives had higher (P<0.001) central aortic BP and pulse wave velocity versus normotensives and exhibited (1) a blunted tissue oxygen saturation response during occlusion, with slower (P=0.006) deoxygenation rate, suggesting reduced muscle oxidative capacity, and (2) a slower reoxygenation rate and blunted hyperemic response (P<0.05), showing reduced microvascular reactivity. Muscle oxygenation responses were correlated with aortic systolic and pulse pressure and augmentation index (P<0.05; age and body mass index (BMI) adjusted). When exercising at the same submaximal intensity, hypertensives required a significantly greater (P<0.001) increase in BP for achieving similar muscle oxygenation levels as normotensives. This response was correlated with the magnitude of microvascular hyperemia and aortic BP. In conclusion, nontreated patients with hypertension exhibit prominent reductions in in vivo indices of skeletal muscle oxidative capacity, suggestive of mitochondrial dysfunction, and blunted muscle microvascular reactivity. These dysfunctions were associated with higher aortic systolic BP and arterial stiffness. Dysregulations in muscle oxygen delivery/utilization and microvascular stiffness, in hypertensive patients, partially contribute to their exaggerated BP during exercise.