1. Cortisol metabolism in human forearm tissues has been investigated by measurement of arteriovenous plasma differences. 2. There were no detectable differences in plasma cortisol concentration in fifty-four pairs of arterial and venous samples collected from twenty subjects at rest, nor in experiments in which 5 mg of cortisol was infused intravenously over a period of 30 min. 3. When [3H]cortisol was infused intra-arterially into the forearm for 10 min, radiochemical analysis of paired arterial and venous samples provided evidence for retention of cortisol in the local tissues and subsequent release into the venous effluent, and conversion of a small fraction of the infused cortisol into a substance chromatographically similar to cortisone. 4. It was demonstrated by the use of 125I-labelled albumin as a plasma marker that retention of the cortisol was due to penetration of the tissues by cortisol and not to a prolonged transit time in the vascular bed.