Clonidine is an antihypertensive drug that markedly suppresses plasma catecholamine levels. In an attempt to investigate the effects of suppression of endogenous catecholamine secretion on glucose homeostatis and glucoregulatory hormones, we administered oral clonidine to 20 normal male subjects, two patients with transsections of the cervical spinal cord, and one patient with an insulinoma. Unexpectedly, after a single dose of 0.5 mg given to normal subjects, insulin concentrations fell and plasma glucose rose 12 ± 1 mg/dl (p < 0.001; n = 6) without an increase in glucagon. After four days of clonidine treatment, plasma glucose again was elevated (Δ = +11 ± 3 mg/dl; p < 0.01), while basal plasma insulin and glucagon levels remained unchanged. The acute insulin response to an intravenous glucose injection of 5 gm decreased from 33 ± 7 to 11 ± 2 μU/ml (n = 8; p < 0.01), and KG declined from 0.80 ± 0.13 to 0.53 ± 0.06% per minute (p < 0.01). Similar responses were seen in the paraplegic patients. In contrast, expected responses to clonidine were not observed in the insulinoma patient preoperatively; these normal responses were restored after resection of the tumor. All metabolic alterations induced by clonidine were reversed by infusion of phentolamine, an alpha-adrenergic blocking agent. We conclude that clonidine causes hyperglycemia and inhibits insulin secretion through an alpha-adrenergic mechanism. Since plasma catecholamine concentrations and vascular tone were markedly recorded by clonidine, this drug appears to selectively stimulate metabolic adrenergic pathways different from those operative in vasomotor regulation.