Phenylephrine increases mean arterial pressure (MAP) by enhanced total peripheral resistance (TPR) but near-infrared spectroscopy (NIRS) determined muscle oxygenation (S_mO₂) increases. We addressed that apparent paradox during supine rest and head-up tilt (HUT). Variables were determined ± phenylephrine in males during supine rest (n = 17) and 40° HUT (n = 7). MAP, stroke volume (SV), heart rate (HR), and TPR were derived by Modelflow^® and NIRS determined biceps S_mO₂ and (tibial) bone oxygenation (S_tibialO₂). For ten subjects, cardiac filling and the diameter of the inferior caval vein (ICV collapsibility index: ((ICV_expiration − ICV_inspiration)/ICV_expiration) × 100) were assessed by ultrasound. Pancreatic polypeptide (PP) and atrial natriuretic peptide (proANP) in plasma were determined by immunoassay. Brachial artery blood flow was assessed by ultrasound and skin oxygenation (S_skinO₂) monitored by white light spectroscopy. Phenylephrine increased MAP by 34% and TPR (62%; P < 0.001) during supine rest. The ICV collapsibility index decreased (24%; P < 0.001) indicating augmented cardiac preload although volume of the left atrium and ventricle did not change. SV increased (18%; P < 0.001) as HR decreased (24%; P < 0.001). ProANP increased by 9% (P = 0.002) with unaffected PP. Brachial artery blood flow tended to decrease while S_skinO₂ together with S_tibialO₂ decreased by 11% (P = 0.026) and 20% (P < 0.001), respectively. Conversely, phenylephrine increased S_mO₂ (9%) and restored the HUT elicited decrease in S_mO₂ (by 19%) along with SV (P = 0.02). Phenylephrine reduces skin and bone oxygenation and tends to reduce arm blood flow, suggesting that the increase in S_mO₂ reflects veno-constriction with consequent centralization of the blood volume.