Background: Some patients complain that eating lettuce, gives them gas and abdominal distention. Our aim was to determine to what extent the patients' assertion is sustained by evidence. Methods: An in vitro study measured the amount of gas produced during the process of fermentation by a preparation of human colonic microbiota (n = 3) of predigested lettuce, as compared to beans, a high gas-releasing substrate, to meat, a low gas-releasing substrate, and to a nutrient-free negative control. A clinical study in patients complaining of abdominal distention after eating lettuce (n = 12) measured the amount of intestinal gas and the morphometric configuration of the abdominal cavity in abdominal CT scans during an episode of lettuce-induced distension as compared to basal conditions. Key Results: Gas production by microbiota fermentation of lettuce in vitro was similar to that of meat (P = .44), lower than that of beans (by 78 ± 15%; P < .001) and higher than with the nutrient-free control (by 25 ± 19%; P = .05). Patients complaining of abdominal distension after eating lettuce exhibited an increase in girth (35 ± 3 mm larger than basal; P < .001) without significant increase in colonic gas content (39 ± 4 mL increase; P = .071); abdominal distension was related to a descent of the diaphragm (by 7 ± 3 mm; P = .027) with redistribution of normal abdominal contents. Conclusion and Inferences: Lettuce is a low gas-releasing substrate for microbiota fermentation and lettuce-induced abdominal distension is produced by an uncoordinated activity of the abdominal walls. Correction of the somatic response might be more effective than the current dietary restriction strategy.