In the rat, about 80% of the intestinal content of secretin immunoreactivity is found distal to the duodenum with a peak in the ileum. This work therefore studied whether the secretin immunoreactivity in distal ileum could be released by substances normally found in the intestinal lumen. An isolated loop of ileum or duodenum was perfused with 100 mM HCl, 3 mM HCl, 50 mM taurocholate, 50 mM oleate, 308 mM glucose, 273 mM amino acids, or 308 mM NaCl in anesthetized rats. Release of secretin immunoreactivity was estimated by the integrated response above basal in portal blood. Substantial release of secretin immunoreactivity was seen after both ileal and duodenal perfusion with concentrated HCl and taurocholate, whereas perfusion with oleate was followed by a lesser response. The response to taurocholate was slower than that to HCl, but more likely represents a physiologic mechanism. The results show that the distal small intestine is capable of contributing to secretin immunoreactivity in the circulation and it is speculated that bile salts and secretin constitute parts of a negative feedback loop.