Introduction - The effect of maximal pharmacological stimulus and physiological systemic hypoxia on blood flow locally within skeletal muscle is elucidated in the present study for the first time in humans. Methods - Seven healthy young men were studied with positron emission tomography. Skeletal muscle blood flow and oxygen consumption as well as several other parameters were measured at rest, during femoral arterial adenosine infusion, in systemic hypoxia (14 % O₂) at rest, and during one-legged dynamic exercise in normoxia and hypoxia without and with adenosine receptor blockade. Whole body VO₂max bicycle test and leg MRI were also performed. Results - Adenosine increased muscle blood flow almost 20-fold at rest and muscle oxygenation was virtually entirely provided by blood flow since oxygen extraction was reduced close to zero. However, blood flow distribution seemed not to change substantially despite large increases in flow. Systemic hypoxia caused significant drop in arterial oxygen saturation from 981 % to 905 % at rest but muscle blood flow remained unchanged while venous oxygen content was reduced as compared to normoxia. There were also significant changes in different parameters due to exercise, but the uptake of energy substrates changed surprisingly little despite substantial changes in blood flow and metabolic conditions. Discussion - Adenosine has potential to increase muscle blood flow extensively, but systemic hypoxia corresponding 3000 m above sea level appears to have little effect on blood flow locally in skeletal muscle.