Background & Aims: We have previously shown that patients with irritable bowel syndrome (IBS) have impaired transit of intestinal gas loads. Because abnormal gas retention can be experimentally reproduced in healthy subjects by pharmacological inhibition of gut motility, we hypothesized that impaired gas transit and retention can be reciprocally corrected by pharmacologically stimulating intestinal propulsion. Methods: In 28 patients with abdominal bloating (14 IBS, 14 functional bloating) and in 14 healthy subjects, gas evacuation and perception of jejunal gas infusion (12 mL/min) were measured. After 2 hours, in 20 patients we tested the effect of intravenous neostigmine (0.5 mg) vs. intravenous saline administered blindly and randomly at a 1-hour interval. Results: After 2 hours of gas infusion, patients with IBS and functional bloating alike exhibited significant gas retention (418 ± 86 mL), abdominal symptoms (2.7 ± 0.5 score), and objective distention (8 ± 2 mm girth increment), in contrast to healthy controls, who experienced none (46 ± 102 mL retention, 0.4 ± 0.3 symptom score, and 3 ± 1 mm distention; P < 0.05 for all). Neostigmine produced immediate clearance of gas retained within the gut (603 ± 53 mL/30 minutes vs. 273 ± 59 mL/30 minutes after saline; P < 0.05) and by 1 hour reduced gas retention (by 373 ± 57 mL), abdominal symptoms (by 1.1 ± 0.5 score), and distention (by 6 ± 1 mm; P < 0.05 for all), whereas intravenous saline produced no effects. Conclusions: In patients with intestinal gas retention, pharmacological stimulation of intestinal propulsion improves gas transit, abdominal symptoms, and distention.