Vitamin D deficiency is common in Crohn's disease (CD). High-dose vitamin D had anti-inflammatory effects in preclinical studies and trials of patients with CD. We performed a randomized trial to determine whether high-dose vitamin D prevents postoperative recurrence of CD after ileocolonic resection.Patients with CD following ileocolonic resection with ileocolonic anastomosis were randomly assigned to groups given weekly 25,000 IU oral vitamin D (n=72) or placebo (n=71) for 26 weeks, at 17 hospitals in the Netherlands and Belgium from February 2014 through June 2017. Patients were assessed at baseline and week 2, 6, 12, and 26 for laboratory and clinical parameters, and underwent ileocolonoscopy at 26 weeks. The primary endpoint was endoscopic recurrence (modified Rutgeerts score ≥i2b, assessed by blinded readers) at 26 weeks. Secondary endpoints included clinical recurrence (Crohn's disease activity index ≥ 220), quality of life (measured by SF-36, IBD-Q and EQ-5D) and outcomes associated with baseline serum concentration of vitamin D.In the vitamin D group, serum levels of 25-hydroxy vitamin D increased from median 42 nmol/L at baseline to 81 nmol/L at week 26 (P<0.00001), whereas levels did not change significantly in the placebo group and remained unchanged at 43 nmol/L. In the intention-to-treat analysis, the the proportion of patients with endoscopic recurrence at 26 weeks did not differ significantly between the vitamin D vs the placebo group (58% vs 66%; P=.37). The cumulative rate of clinical recurrence did not differ significantly between the groups (18.1% in the vitamin D group vs 18.3% in the placebo group; P=.91). Quality of life improved slightly over time in both groups but did not differ significantly between groups (P=.07). There were few adverse events in either group.High-dose vitamin D, compared with placebo, did not reduce the incidence of postoperative endoscopic or clinical recurrence of CD in patients who underwent ileocolonic resection with ileocolonic anastomosis. ClinicalTrials.gov no: NCT02010762.