1. Morphine suppresses the release of pancreatic polypeptide, a hormone under vagal cholinergic control. The intention of the study was to detect whether the mu-opiate receptor agonist loperamide is also able to inhibit pancreatic polypeptide release, and to define its site of action. 2. In groups of healthy subjects (n = 6 each) stimulation of pancreatic polypeptide was assessed in five different tests: (i) insulin-hypoglycaemia; (ii) modified sham feeding; (iii) intravenous infusion of the cholecystokinin analogue ceruletide; (iv) injection of corticotropin releasing hormone; (v) infusion of the muscarinic acetylcholine agonist bethanechol. All tests were performed after oral application of either a placebo or loperamide (16 mg), tests (ii) and (iii) were repeated with loperamide in smaller doses (2 and 6 mg), with loperamide plus naloxone, with naloxone alone, and with infusion of atropine. Plasma concentrations of pancreatic polypeptide were measured radioimmunologically. 3. Release of pancreatic polypeptide in test (i) to (iv) was completely blocked by 16 mg loperamide, whereas bethanechol-stimulated release (test 5) was not influenced. Tests (ii) and (iii) showed that the inhibition was dose-dependent and could be attenuated by naloxone. The inhibitory effect of loperamide was comparable with that of atropine. 4. We conclude that loperamide causes a dose-dependent inhibition of pancreatic polypeptide release mediated by vagal-cholinergic pathways, but does not have an atropine-like peripheral action.