Paediatric patients with Crohn’s disease (n = 297, initiating infliximab or adalimumab, mean age 13.9 years) were randomly assigned to receive methotrexate or placebo and followed for 12–36 months. Combination therapy with methotrexate in the adalimumab-initiator group showed a twofold reduction in treatment failure (HR 0.40, 95% CI 0.19–0.81) compared with monotherapy (placebo group) but not in the infliximab-initiator group (HR 0.93, 95% CI 0.55–1.56). Combination therapy resulted in more adverse effects but fewer serious ones than monotherapy.