Pediatric multiple sclerosis (MS) with manifestations before 16 years of age occurs in 0.4–10.5% of whole MS population. The initial course of the disease is relapsing–remitting with a relapse rate generally higher than that of adults, less than 3% have a primary progressive form. Some recent reports have shown that Interferon β (IFNβ) has a strong effect in reducing the relapse rate in children with MS and is well tolerated. We report a 12-year-old girl with MS and a high relapse rate from the onset. Frequent magnetic resonance imaging (MRI) detected persisting inflammatory activity and increase of lesion burden. She continued to present acute relapses and progression of disability in spite of a treatment with IFNβ-1a at different dosages and the addition of pulse IV steroid treatment. Then, we opted for Natalizumab treatment, recently approved as a monotherapy for patients with MS who experienced inadequate response to other disease modifying therapies and never used till now in pediatric MS. Our patient showed a complete response to Natalizumab with clinical and MRI suppression of disease activity.