The morphology and distribution of secretin (S) cells were investigated in human and dogs. S cells were well-visualized by the indirect immunofluorescence antibody technique, using a highly specific rabbit anti-secretin sera. The fluorescence reaction was not blocked by an excess amount of gastrin, cholecystokinin, glucagon, vasoactive intestinal polypeptide, or motilin, whereas secretin blocked the reaction. S cells were seen in the mucosa of the antrum and duodenum in both humans and dogs and throughout the entire length of the canine small intestine. They were not in the mucosa of the esophagus, fundus of the stomach or rectum. These cells were either pyramidal in shape or pear-shaped and were 1/3 of the size of gastrin cells. The possible significance of S-cell distribution in the antrum and small intestine is discussed.