Awareness of the factors influencing discontinuation of immunomodulatory drugs (IMD) treatment in multiple sclerosis (MS) can help to find approaches to patient management with the aim of establishing more specific indications and also attaining more optimal patient selection in future clinical trials. To identify the causes that influence adhesion to IMD therapy within the clinical practice in a large cohort of patients with MS. We have studied all MS patients who have initiated IMD in our hospital. All patients took part in training sessions where treatment expectations and side effects were explained and they received training in the administration technique. Reasons for stopping therapy were recorded during follow-up. We studied 632 MS patients (mean follow-up was 47.1 (28.7) months). At the time of analysis, 107/632 patients (17%) were no longer receiving IMD. Almost half of the patients who stopped IMD (52/107) did so within the first two years on therapy. Fifty-six patients stopped IMD because of lack of efficacy. Only 27 patients (4.3%) discontinued treatment for reasons other than inefficacy or side effects. The proportion of patients with secondary progressive MS that stopped IMD therapy was 30%, while only 13.5% of the patients with relapsing remitting MS stopped therapy (P < 0.0001). Expanded Disability Status Scale (EDSS) score at entry was the main factor that predicted interruption of therapy. The proportion of patients interrupting IMD in our centre is low, possibly due to individualized care. Higher EDSS, mainly in the first two years of treatment, is the main factor related with interruption. Close follow-up of these patients would be useful in avoiding early discontinuation of therapy.