Background: Crohn’s disease (CD) is a chronic, relapsing, inflammatory bowel disease. Up to 65% of patients with CD require an operation to control the disease within 10 years. Both endoscopic and clinical recurrence is common within 2 years of operation, with re-operation rates cumulating at 5% of patients per year. Objectives: This study assessed if the use of mercaptopurine (MP) can prevent or delay postoperative recurrence in CD. Design: An individually randomised, multicentre, double-blind, placebo-controlled trial with follow-up at 6, 13, 31, 49, 67, 85, 103, 121, 139 and 157 weeks. Setting: Twenty-nine tertiary referral hospitals in the UK. Participants: Those aged ≥ 16 years in Scotland (or aged ≥ 18 years in England and Wales) with a histologically confirmed diagnosis of CD (according to the Lennard-Jones criteria) and surgical intervention ≤ 3 months prior to randomisation to remove all observable disease at ileocolonic or small bowel resections. Patients were excluded if they had a known intolerance of or hypersensitivity to thiopurines; were known to require further surgery; underwent strictureplasty alone; had a stoma; or had an active or untreated malignancy or absent thiopurine S-methyltransferase (TPMT) activity. Prior to randomisation any postoperative infections were fully treated and existing treatments for CD were stopped. Intervention: Daily oral dose of MP or placebo, with dose adjusted according to body weight (kg) and TPMT status. Blood samples for genetic and serological analysis were taken at randomisation with additional blood and stool samples collected at weeks 0, 13, 49, 103 and 157 for central analysis of drug metabolite and faecal calprotectin levels, with endoscopic assessment at weeks 49 and 157. Main outcome measures: The primary end point was clinical recurrence of CD (Crohn’s Disease Activity Index score of > 150 points plus 100-point rise) and the need for anti-inflammatory rescue therapy or primary surgical intervention. Secondary end points included faecal calprotectin and thioguanine levels, and assessment of endoscopic recurrence. The primary analysis was adjusted for baseline values of previous treatment with MP and azathioprine, with the adjusted analysis considered to be the primary analysis. Results: Between June 2008 and April 2012, 240 patients were enrolled and received at least one dose of the study drug. A total of 128 (53%) participants were randomised to receive MP and 112 (47%) to receive placebo. No randomised patients were excluded from the analysis. More patients achieved the primary end point in the placebo group (n = 26, 23.2%) than in the MP group (n = 16, 12.5%), with an adjusted p-value of 0.073 [hazard ratio (HR) 0.535, 95% confidence interval (CI) 0.27 to 1.06]. Of the smokers on MP, 3 out of 29 (10.3%) had clinical recurrence versus 12 out of 26 (46.2%) on placebo, demonstrating that MP was effective at preventing postoperative recurrence in smokers (HR 0.127, 95% CI 0.04 to 0.46) but not in non-smokers (HR 0.898, 95% CI 0.42 to 1.94). The proportion of patients experiencing adverse events was similar in the treatment and placebo groups. Limitations: There was a lower than anticipated primary event rate (12.5% in the treatment group vs. 23.2% in the placebo group, as opposed to expected rates of 30% vs. 50%). Conclusions: The Trial Of Prevention of Post operative Crohn’s disease (TOPPIC) is the largest single, double-blind trial assessing the use of thiopurines to prevent postoperative recurrence in CD. From the trial itself, MP was not effective in reducing the frequency of clinical postoperative recurrence of CD overall, but the data suggest that it has clinically meaningful effect among the subgroup of patients who continue to smoke after surgery.