In contrast to supramaximal CCK8 or caerulein, acute or prolonged supraphysiological levels of endogenous cholecystokinin (CCK58) do not cause pancreatitis. Compared to CCK8, CCK58 is a much stronger stimulant of pancreatic chloride and water secretion, equivalent to maximally effective secretin, but with a chloride to bicarbonate ratio characteristic of acinar fluid. Because supraphysiological endogenous cholecystokinin does not cause pancreatitis and because co-administration of secretin ameliorated caerulein- or CCK8-induced pancreatitis, coincident with restoring pancreatic water secretion, we hypothesized that supramaximal CCK58 would not induce pancreatitis. Conscious rats were infused i.v. with 2 or 4 nmol·kg^-1·h^-1 of CCK8 or synthetic rat CCK58 for 6 h and pancreases examined for morphological and biochemical indices of acute pancreatitis. A second group was treated as above while monitoring pancreatic protein and water secretion. CCK8 at 2 nmol·kg^-1·h^-1 caused severe edematous pancreatitis as evidenced by morphological and biochemical criteria. CCK58 at this dose had minimal or no effect on these indices. CCK58 at 4 nmol·kg^-1·h^-1 increased some indices of pancreatic damage but less than either the 2 or 4 nmol·kg^-1·h^-1 dose of CCK8. Pancreatic water and protein secretion were nearly or completely abolished within 3 hr of onset of CCK8 infusion, whereas water and protein secretion were maintained near basal levels in CCK58-treated rats. We hypothesize that supramaximal CCK58 does not induce pancreatitis because it maintains pancreatic acinar chloride and water secretion, which are essential for exocytosis. We conclude that CCK-58 may be a valuable tool for investigating events that trigger pancreatitis.