Background: Corticotropin releasing factor (CRF), a mediator of stress response, alters gastrointestinal (GI) functions. Stress-related changes in colonic motility are blocked by selective CRF₁-receptor antagonists. Aim: To assess whether modulation of central and peripheral CRF₁ receptors affects colonic transit and bowel function in female patients with diarrhea-predominant irritable bowel syndrome (D-IBS). Methods: This randomized, double-blind, placebo-controlled, two week study evaluated the effects of oral pexacerfont (BMS-562086), a selective CRF1-receptor antagonist, 25 and 100 mg q.d., on GI and colonic transit of solids (by validated scintigraphy with primary endpoint colonic geometric center [GC] at 24 h) and bowel function (by validated daily diaries) in 39 women with D-IBS. The 100mg dose was comparable to a dose that inhibited colonic motility in stressed rats. Treatment effects were compared using ANCOVA with baseline colonic transit as covariate. Study had 80% power (=0.05) to detect clinically meaningful (26%) differences in colonic transit. Results: 39 of 55 patients fulfilled eligibility criteria (9 screen failures, 5 baseline GC24 outside pre-specified range). At baseline, three treatment groups had comparable age, BMI, and GC 24 h. Significant effects of pexacerfont relative to placebo were not detected on colonic GC24 (p=0.53), gastric emptying, orocecal transit, ascending colon emptying t1/2, stool frequency, consistency and ease of passage. No safety issues were identified. Conclusions: In women with D-IBS, pexacerfont, 25 or 100 mg QD, does not significantly alter colonic or other regional transit or bowel function. The role of central and peripheral CRF₁ receptors in bowel function in IBS-D requires further study.