The main objective of this study is to evaluate the effect of immunomodulatory agents (IMAs) (Interferon-Beta, Glatiramer Acetate) in a large cohort of multiple sclerosis (MS) patients with disease onset in childhood or adolescence, treated before 16 years of age, after a long-term follow-up. A total of 130 patients were identified, 77 were treated with Avonex, 39 with Rebif/Betaferon, 14 with Copaxone. After a mean (SD) treatment duration of 53.6 ± 27.0, 59.9 ± 39.5 and 74.6 ± 35.5 months, respectively, the relapse rate decreased significantly. The final EDSS score was unchanged with respect to the initial score. Similar results were also observed in subjects who continued a long-term follow-up after they were included in an observational study in 2004, and in subjects who were treated before 12 years of age. The frequency of clinical and laboratory adverse events was similar to that observed in adult patients. To conclude, IMAs were effective and well tolerated in paediatric patients with MS.