Emptying of the human gall-bladder has previously been shown to be associated with the release of motilin, both in the fasting state and after various stimuli, such as oral intake of fat or water. Whether motilin causes emptying of the human gall-bladder or whether the peptide is released by gall-bladder emptying is not presently known. Recent animal experiments suggest that intravenous infusion of pure porcine motilin causes emptying of the gall-bladder, both in the pig and the dog. In the present investigation, neither a physiological nor a pharmacological one-hour infusion of pure porcine motilin caused emptying of the human gall-bladder. In contrast, manual compression of the gall-bladder, at the beginning of operation for large bowel carcinoma, was followed by motilin release. The one-hour integrated motilin response after gall-bladder compression was about 10 times greater than in the control patients in whom the motilin response after palpation of the liver was similarly calculated. We conclude that flow of bile into the proximal small bowel is a signal for the release of motilin from the peptide-producing cells in the gut mucosa.