Methotrexate (MTX) is widely used as a primary maintenance medication in children with Crohn’s disease (CD), despite a lack of data supporting this practice. Researchers sought to evaluate the efficacy of MTX as the “first” primary maintenance therapy and identify baseline predictive characteristics in children with newly diagnosed mild/moderate CD. Single-center 10-year follow-up of newly diagnosed CD patients who were initially maintained on MTX. Patients with a durable response or clinical remission at baseline were compared to those who progressed to anti-TNF medication within a year. To be considered in remission, the Pediatric Crohn’s Disease Activity Index (PCDAI) has to be less than equal to 10. Researchers found 65 patients (mean age, 11.8 years; 72% male; mean ± SD PCDAI, 17.8±10.5) who began MTX less than 4 months after diagnosis as their primary maintenance therapy. Corticosteroids (CS) (54/65), a defined diet (4-65), and a combination of CS and diet (6-65) were the first line of treatment before MTX was introduced. A mean oral dose of 11.4 mg/m2 and a mean subcutaneous dose of 12.5 mg/m2 were employed. About 1 year after induction, 81% of patients were in steroid-free remission, and 32 of 36 patients on MTX monotherapy achieved clinical remission. At 1 year, 14 (39%) of the 36 patients on MTX had gross mucosal healing (22% of the original group). About 10 more patients experienced mucosal improvement (37% of total healed/improved). About 15 patients (23%) experienced early failure and were switched to anti-TNF (tumor necrosis factor) for less than equal to 4 months. PCDAI, hemoglobin, ESR, albumin, and mode of administration at baseline were not predictive of the outcome. In their cohort, MTX was well tolerated in their cohort, with only 1 patient discontinuation due to increased aminotransferases. During the 1-year follow-up, no patient required CD surgery. In mild/moderate CD, MTX may have a primary maintenance function.