Background & Aims: We hypothesized that lipids, which induce various motor and sensory effects on the gut, modulate intestinal gas dynamics and that alteration of this regulatory mechanism may result in impaired gas transit in patients with irritable bowel syndrome (IBS). Methods: In 45 healthy subjects and 30 patients with IBS, evacuation of gas infused into the jejunum (at 12 mL/min) was measured for 2 hours. The effect of simultaneous duodenal perfusion of lipids at 0 kcal/min (saline), 0.5 kcal/min, and 1 kcal/min was tested in groups of 15 subjects each. Results: In healthy subjects, duodenal lipids at 1 kcal/min but not at 0 kcal/min or 0.5 kcal/min produced significant gas retention (281 ± 53 mL vs. 22 ± 64 mL at 0 kcal/min and -65 ± 72 mL at 0.5 kcal/min; P < 0.05 for both). Patients with IBS exhibited gas retention during saline perfusion (259 ± 85 mL at 0 kcal/min; P < 0.05 vs. healthy subjects) and were hypersensitive to duodenal lipids (505 ± 61 mL retention at 0.5 kcal/min; P < 0.05 vs. saline and vs. healthy subjects). The "gas plus lipids" challenge test discriminated patients with 100% sensitivity and 93% specificity. Conclusions: Physiologic concentrations of intestinal lipids exert an inhibitory control on intestinal gas transit, and this mechanism is up-regulated in patients with IBS. Hence, impaired gas propulsion, shown by the gas challenge test, may be useful as a diagnostic test if replicated in a larger series of patients.