BACKGROUND AND AIMS: Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) have been found to have increased postprandial levels of serotonin (5-HT). Functional dyspepsia (FD) and IBS have been proposed to have common methods of pathogenesis, but little is known about the role of 5-HT in FD. METHODS: We measured postprandial levels of 5-HT in 54 patients with FD (based on Rome III criteria) and 28 asymptomatic healthy individuals (controls). Patients with gastroesophageal reflux disease and IBS as their predominant symptom were excluded. After an overnight fast, the subjects drank a liquid meal (Ensure®, 1.06 kcal/ml at 30 ml/min) and underwent a (13)C-octanoic acid breath test to measure gastric emptying times. Blood samples were collected at 0, 30, 60, 90, 120 min after the liquid meal for the 5-HT assay. RESULTS: Thirty-five with FD (65%) had postprandial distress syndrome (PDS) and 6 (11%) had a combination of PDS and epigastric pain syndrome (EPS). There were no differences in rates of gastric emptying between patients with FD (103.6∓19.4 min) and controls (83.1∓4.0 min; P =.30). However, patients with FD had lower caloric intake (823.40∓44.1 kcal) than controls (1021∓68.2 kcal; P =.026). Patients with FD also had lower basal ( P =.03) and postprandial plasma levels of serotonin at 30 min ( P =.04), 60 min ( P =.01), and 90 min ( P =.02), 120 min ( P =.002) than controls, as well area under the curve values over the 120-min time period ( P =.005). Repeated measures of analysis of variance correlated 5-HT level with FD ( P <.001). CONCLUSIONS: In contrast to patients with IBS-D, those with FD have decreased basal and postprandial plasma levels of 5-HT. These findings indicate that the pathogenic mechanism of FD differs from that of IBS-D, and that strategies to alter 5-HT levels or activity might be developed to treat patients with FD.