Serum dopamine beta-hydroxylase (DBH) activity was comparable in eight adrenalectomized patients and in 41 normal volunteers (37.8 +/- 3.6 vs. 40.0 +/- 4.0 IU), but were very low in four patients with severe diabetic autonomic neuropathy (6.7 +/- 4.2). These observations suggest that the major source of DBH activity in human serum is probably the sympathetic nervous system. Serum DBH activity was also significantly lower in seven patients with low renin essential hypertension than in 17 patients with normal renin hypertension (19.9 +/- 4.3 vs. 43.9 +/- 5.0 IU, P less than 0.05). Dietary sodium depletion, a stimulus for catecholamine secretion, produced only a small increase in serum DBH activity in supine normal volunteers (26.5 +/- 10.4 to 33.9 +/- 11.4, P less than 0.05; n = 7) and in five adrenalectomized patients (33.0 +/- 12.7 to 44.1 +/- 15.2, P = 0.06). Plasma renin activity increased more than 3-fold in these same subjects, and did not correlate with serum DBH activity. Similarly, 4 hours of ambulation produced only a small increase in serum DBH activity which did not correlate with plasma renin activity. The small magnitude of these responses to physiological stimuli of the sympathetic nervous system diminishes the potential clinical usefulness of measurement of serum DBH activity. Further studies utilizing direct correlation of plasma and urine catecholamines with serum DBH activity are needed to establish its relationship to sympathetic nervous system activity.