The effect of intravenous administration of melatonin on the efferent activity of the adrenal nerve was investigated in the rat. Intravenous infusion of 1 or 2 ng melatonin resulted in a decrease, and 10 or 20 ng or larger amount of melatonin caused an increase in the efferent activity of the adrenal nerve. The least effective dose for the suppressive activity of melatonin was 100 pg and the response is dose-related. Administration of either 1 ng or 10 ng of melatonin did not change the plasma glucose concentration until 30 min after the administration. Hepatic vagotomy eliminates the inhibitory effect of melatonin. These results suggest that melatonin sensors in the hepato-portal region and melatonin receptors in the SCN play important roles in the regulation of sympathetic outflow to the adrenal medulla.