The effect of increased tissue pressure on blood flow in subcutaneous and skeletal muscle tissue was studied in 8 healthy humans resting in horizontal position. Blood flow was measured by the local 133Xe washout technique in the mid-calf region. Tissue pressure in the depot area was increased by inflating a compression cuff, 50 cm wide (knee to ankle). Blood flow rates were obtained from compressed tissues with normal vasomotor tone, at papaverine-induced vasoparalysis and during distension of the compressed vessels. The latter was achieved by inflating a proximal (extra) compression cuff on the thigh 10 or 20 mmHg above the pressure level in the more distally placed compression cuff. Increased tissue pressure was a potent stimulus for arteriolar dilatation (autoregulation) in both tissues. The autoregulatory response was to some extent counteracted by an increase in local vascular resistance in the postcapillary section as evidenced by the results of simultaneous venous stasis. Blood flow ceased in vasoparalysed tissues as well as in tissues with normal vasomotor tone, when the compression cuff was inflated to the level of the local diastolic blood pressure. Maintaining external compression at the diastolic blood pressure level, blood flow reappeared in both tissues, when the compressed vessels were distended by adding the proximal (extra) compression. It is concluded, that blood flow cessation in compressed tissues is caused by a widespread arterial-arteriolar collapse in diastole, as the volume of blood injected during the systolic peak is too small to expand also the distal sections of the precapillary vessels.