SummaryBackgroundOndansetron may be beneficial in irritable bowel syndrome with diarrhoea (IBS‐D).AimTo conduct a 12‐week parallel group, randomised, double‐blind, placebo‐controlled trial of ondansetron 4 mg o.d. (titrated up to 8 mg t.d.s.) in 400 IBS‐D patients. Primary endpoint: % responders using the Food and Drug Administration (FDA) composite endpoint. Secondary and mechanistic endpoints included stool consistency (Bristol Stool Form Scale) and whole gut transit time (WGTT). After literature review, results were pooled with other placebo‐controlled trials in a meta‐analysis to estimate relative risks (RR), 95% confidence intervals (CIs) and number needed to treat (NNT).ResultsEighty patients were randomised. On intention‐to‐treat analysis, 15/37 (40.5%; 95% CI 24.7%–56.4%) met the primary endpoint on ondansetron versus 12/43 (27.9%; 95% CI 14.5%–41.3%) on placebo (p = 0.19). Ondansetron improved stool consistency compared with placebo (adjusted mean difference − 0.7; 95% CI −1.0 to−0.3, p < 0.001). Ondansetron increased WGTT between baseline and week 12 (mean (SD) difference 3.8 (9.1) hours, versus placebo −2.2 (10.3) hours, p = 0.01). Meta‐analysis of 327 patients from this, and two similar trials, demonstrated ondansetron was superior to placebo for the FDA composite endpoint (RR of symptoms not responding = 0.86; 95% CI 0.75–0.98, NNT = 9) and stool response (RR = 0.65; 95% CI 0.52–0.82, NNT = 5), but not abdominal pain response (RR = 0.95; 95% CI 0.74–1.20).ConclusionsAlthough small numbers meant the primary endpoint was not met in this trial, when pooled with other similar trials meta‐analysis suggests ondansetron improves stool consistency and reduces days with loose stool and urgency.Trial registration – http://www.isrctn.com/ISRCTN17508514