To study interactions between hydrochloric acid and fatty acids on pancreatic secretion, six dogs with chronic gastric, pancreatic, and small intestinal cannulas received various combinations of the following intestinal perfusates: 20, 40, and 80 mM hydrochloric acid, oleate, dodecanoate, or 0.15 M saline. Regional intestinal perfusion (a proximal segment measuring 45 cm from the pancreatic duct versus the remaining small bowel) was utilized to separate the aqueous acid and lipid solutions. Both oleate and dodecanoate augmented the bicarbonate output induced by intraluminal acidification. In other experiments, intraluminal oleate, when combined with exogeneous intravenous secretin (12.5-900 ng . kg-1 . h-1), potentiated the secretin-induced bicarbonate output at low secretin doses. Dodecanoate also increased secretin-induced bicarbonate output. In all of these studies, protein outputs were increased by intestinal fatty acids. It is concluded that intestinal fatty acids can enhanced acid-induced canine pancreatic secretion.