BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) might have other underlying pathologies. Pancreatic disease can be elusive especially in the early stages, and some symptoms overlap with those of IBS. We evaluated the prevalence of exocrine pancreatic insufficiency in diarrhea-predominant IBS (D-IBS) and assessed the effects of pancreatic enzyme supplementation. METHODS: The study included patients who met the Rome II criteria for D-IBS, patients with chronic diarrhea, and subjects without diarrhea (controls). Subjects' baseline weight, stool frequency, stool consistency (using the Bristol score), and fecal elastase-1 (Fel-1) levels were determined. Patients were assessed using British Society of Gastroenterology IBS guidelines. Patients with Fel-1 levels less than 100 mu g/g stool (indicating pancreatic exocrine insufficiency; group 1) were compared with age- and sex-matched patients with D-IBS and normal levels of Fel-1 (group 2), given pancreatic enzyme therapy, and reassessed at 12 weeks. RESULTS: Fel-1 levels were less than 100 mu g/g in stool from 19 of 314 patients with D-IBS (6.1%; 95% confidence interval [Cl], 3.7%-9.3%), none of the 105 patients with chronic diarrhea (95% Cl, 0.0%-3.5%), and none of 95 controls (95% CI, 0.0-3.8%) (P < .001). After enzyme supplementation, improvements in stool frequency (P < .001), stool consistency (P < .001), and abdominal pain (P = .003) were observed in patients in group 1, but not in group 2. CONCLUSIONS: Pancreatic exocrine insufficiency was detected in 6.1% of patients who fulfilled the Rome II criteria for D-IBS. In these patients, pancreatic enzyme therapy might reduce diarrhea and abdominal pain. Pancreatic exocrine insufficiency should be considered in patients with D-IBS.