Context: The bitter substance quinine modulates the release of a number of gut and gluco-regulatory hormones and upper gut motility. As the density of bitter receptors may be higher in the duodenum than the stomach, direct delivery to the duodenum may be more potent in stimulating these functions. The gastrointestinal responses to bitter compounds may also be modified by sex. Background: We have characterized the effects of intragastric (IG) versus intraduodenal (ID) administration of quinine hydrochloride (QHCl) on gut and pancreatic hormones and antropyloroduodenal pressures in healthy men and women. Methods: 14 men (26±2 years, BMI: 22.2±0.5 kg/m2) and 14 women (28±2 years, BMI: 22.5±0.5 kg/m2) received 600 mg QHCl on 2 separate occasions, IG or ID as a 10-mL bolus, in randomized, double-blind fashion. Plasma ghrelin, cholecystokinin, peptide YY, glucagon-like peptide-1 (GLP-1), insulin, glucagon, and glucose concentrations and antropyloroduodenal pressures were measured at baseline and for 120 minutes following QHCl. Results: Suppression of ghrelin (P=0.006), stimulation of cholecystokinin (P=0.030), peptide YY (P=0.017), GLP-1 (P=0.034), insulin (P=0.024), glucagon (P=0.030), and pyloric pressures (P=0.050), and lowering of glucose (P=0.001) were greater after ID-QHCl than IG-QHCl. Insulin stimulation (P=0.021) and glucose reduction (P=0.001) were greater in females than males, while no sex-associated effects were found for cholecystokinin, peptide YY, GLP-1, glucagon, or pyloric pressures. Conclusion: ID quinine has greater effects on plasma gut and pancreatic hormones and pyloric pressures than IG quinine in healthy subjects, consistent with the concept that stimulation of small intestinal bitter receptors is critical to these responses. Both insulin stimulation and glucose lowering were sex-dependent.