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Highly purified secretin, infused endoportally in five conscious mongrel dogs at a rate of 10 clinical units per min for 20 min, caused a prompt and statistically significant reduction in the pancreaticoduodenal vein level of pancreatic glucagon from a control average of 1130 pg/ml (SEM+/-312) to a nadir of 492 pg/ml (SEM+/-194) 15 min later (P < 0.01). During modest hyperglycemia of about 130 mg/100 ml, induced by glucose infusion, the infusion of secretin at the same rate elicited even more dramatic suppression of pancreaticoduodenal glucagon levels to virtually unmeasurable concentrations. At a lower rate of infusion (5 U priming injection followed by 1 U/min for 20 min) significant suppression of glucagon secretion during hyperglycemia was also observed. Stimulation of endogenous secretin release by the intraduodenal administration of 14 mEq of HCl in 10 dogs during intravenous glucose infusion was followed by a decline in pancreaticoduodenal vein glucagon from 130 pg/ml (SEM+/-34) to a nadir of 99 pg/ml (SEM+/-32) 5 min later (P < 0.05). The infusion of secretin at a rate of 10 U/min in alloxan-diabetic dogs was associated with a significant decline in peripheral venous plasma glucagon, from a mean preinfusion level of 272 pg/ml (SEM+/-39) to a nadir of 128 pg/ml (SEM+/-22) (P < 0.01). It was concluded that exogenous secretin in the doses employed in this study is a potent suppressor of glucagon secretion, particularly during hyperglycemia. HCl-stimulated endogenous secretin also suppresses glucagon secretion. The ability of secretin to augment the glucagon-suppressing effect of ingested glucose qualifies it uniquely for a physiologic role as a modifier of the islet cell response to ingested glucose. The fact that it lowers the hyperglucagonemia of alloxan-diabetic dogs suggests that its glucagon-suppressing activity may not be insulin dependent.