Switching treatment may be beneficial in patients with relapsing-remitting multiple sclerosis (RRMS) who respond inadequately to first-line immunomodulatory therapy. The objective of this study was to evaluate clinical outcomes after switching treatment in such patients. This prospective longitudinal observational study included 114 patients with RRMS who failed first-line monotherapy and were switched treatments after 3 years. Every 3 months, patients underwent a full neurological examination. Outcome was compared between the 3-year Before Switch and After Switch treatment periods. The primary outcome measure was the annualized relapse rate; secondary outcome measures were the proportion of relapse-free patients and the median change in Expanded Disability Status Scale (EDSS). Patients were switched either from low-dose to high-dose interferon-beta (IFNbeta; n = 31), from IFNbeta to glatiramer acetate (GA; n = 52) or mitoxantrone (n = 13), or from GA to IFNbeta (n = 16). In 3 years after switching, annualized relapse rates fell by 57-78% according to the group. The proportion of relapse-free patients varied from 56% to 81%. Least improved was observed in patients switching between INFbeta preparations. Median EDSS scores remained stable in all groups except the GA to IFNbeta switchers. In conclusion, patients who fail first-line immunomodulatory therapy generally benefit from switching to another class of immunomodulatory therapy.