These studies were performed to assess the effects of various exocrine pancreatic stimuli on somatostatin-like immunoreactivity (SLI) secretion in pure rat pancreatic juice. Ingestion of a meal and subcutaneous injections of caerulein (CA), secretin (SE), and their combination (CA + SE) were compared. Basal fasting SLI output over 5 1/2 h averaged 13.7 ng/30 min; the response to feeding resulted in decreased SLI outputs from 9.7 to 1.7 ng/30 min, a reduction of 81%. SLI secretion following CA, SE, and CA + SE was similar to that obtained following feeding but the reductions of 29, 32, and 39% were less marked and of shorter duration. A return to basal SLI levels was observed only 2 1/2 h following CA administration. Increases in pancreatic volume and protein outputs following CA, SE, and CA + SE were comparable to the feeding response although less pronounced. These data indicate that SLI secretion in pure pancreatic juice can be modulated by two peptides and feeding and that its release is reduced when compared with increases in pancreatic volume and protein secretion. The observation that the peptide's response in terms of SLI output as well as protein and volume were in the same range, although less sustained than the response to a meal, indicates that all stimuli used induced a physiological response of the pancreas.