The effect of graded doses of intravenously infused secretin and intestinally perfused sodium oleate and HCl on pancreatic exocrine secretion and plasma secretin was determined in cats and dogs prepared with pancreatic fistulas. The pancreatic dose--response curves for bicarbonate following duodenal perfusion of oleate and HCl in cats were almost identical and paralleled the response to exogenous secretin. Although the bicarbonate response to oleate in dogs was less pronounced than the response to HCl or secretin, the bicarbonate output was observed to increase relative to protein output with increasing doses of the intestinally perfused fat. These observations suggested that secretin or a substance with secretin-like activity may be released from the intestine on contact with fat. The inability to detect changes in secretin immunoreactivity in both cats and dogs with increasing doses of oleate suggests that if secretin is released, it is in amounts undetectable by our radioimmunoassay or that some other unknown substance with secretin-like activity may be released.