The possibility of an action of propranolol which reduces traffic in the sympathetic nervous system and/or reduces release of norepinephrine at sympathetic nerve endings has been investigated in normal subjects. Plasma norephinephrine was measured in resting supine subjects before and during infusions of sodium nitroprusside which reduced the systolic blood pressure by approximately 10 and later by 20 mm Hg. In 5 subjects these observations were repeated 2 hr after a single 200-mg oral dose of propranolol and in 3 they were repeated after 2 to 8 wk of propranolol 320 mg twice daily. In the control experiments, plasma norepinephrine increased from 0.22 up to 0.74 ng/ml when the blood pressure was reduced by 17/15 mm Hg. Corresponding figures 2 hr after 200 mg propranolol were an increase of plasma norepinephrine from 0.30 or 0.79 ng/ml with a reduction of blood pressure of 19/15 mm Hg. After long-term treatment with 640 mg propranolol daily, a similar reduction of pressure with sodium nitroprusside increased plasma norepinephrine from 0.24 to 0.68 ng/ml. There was no significant alteration in the elevation of plasma norepinephrine following blood pressure reduction with nitroprusside after either short- or long-term treatment with propranolol. These experiments do not suggest a significant role for a nervous system effect of propranolol in modifying sympathetic activity.