BACKGROUND & AIMS: Few prospective data are available to support the clinical relevance of mucosal healing in patients with Crohn's disease. This study examined whether complete healing, determined by endoscopy, predicts a better outcome in Crohn's disease. METHODS: One-hundred thirty-three newly diagnosed and treatment-naive Crohn's disease patients were given either a combination of immunosuppressive therapy (azathioprine) and 3 infusions of infliximab or treatment with conventional corticosteroids. Patients given azathioprine were given repeated doses of infliximab for relapses, patients given corticosteroids were given azathioprine in cases of corticosteroid dependency and infliximab only if azathioprine failed. A representative subset of 49 patients from the initially randomized cohort underwent ileocolonoscopy after 2 years of therapy. Correlation analysis was performed between different clinical parameters including endoscopic activity (Simple Endoscopic Score) and clinical outcome 2 years after this endoscopic examination. Data were available from 46 patients 3 and 4 years after therapy began. RESULTS: Complete mucosal healing, defined as a simple endoscopic score of 0 after 2 years of therapy, was the only factor that predicted sustained, steroid-free remission 3 and 4 years after therapy was initiated; it was observed in 17 of 24 patients (70.8%) vs 6 of 22 patients with lesions detected by endoscopy (27.3%, Simple Endoscopic Score > 0) (P = .036; odds ratio = 4.352; 95% confidence interval, 1.10-17.220). Fifteen of 17 patients with mucosal healing at year 2 maintained in remission without further infliximab infusions during years 3 and 4 (P = .032; odds ratio = 4.883; 95% confidence interval, 1.144-20.844). CONCLUSIONS: Complete mucosal healing in patients with early-stage Crohn's disease is associated with significantly higher steroid-free remission rates 4 years after therapy began.