The effectiveness of disease-modifying drugs in the treatment of multiple sclerosis is associated with adherence. RebiSmart (R) electronic device provides useful information about adherence to the treatment with subcutaneous (sc) interferon (IFN) beta-1 alpha (Rebif (R)). The aim of the study was to determine long-term adherence to this treatment in patients with relapsing-remitting multiple sclerosis (RRMS). This retrospective multicentre observational study analysed 258 patients with RRMS who were receiving sc IFN beta-1 alpha (Rebif (R)) treatment by using RebiSmart (R) until replacement (36 months maximum lifetime) or treatment discontinuation. Adherence was calculated with data (injection dosage, time, and date) automatically recorded by RebiSmart (R). Patients in the study had a mean age of 41 years with a female proportion of 68%. Mean EDSS score at start of treatment was 1.8 (95% CI, 1.6-1.9). Overall adherence was 92.6%(95% CI, 90.6-94.5%). A total of 30.2% of patients achieved an adherence rate of 100%, 80.6% at least 90%, and only 13.2% of patients showed a suboptimal adherence (<80%). A total of 59.9% of subjects were relapse-free after treatment initiation. Among 106 subjects (41.1%) who experienced, on average, 1.4 relapses, the majority were mild (40.6%) or moderate (47.2%). Having experienced relapses from the beginning of the treatment was the only variable significantly related to achieving an adherence of at least 80% (OR = 3.06, 1.28-7.31). Results of this study indicate that sc IFN beta-1 alpha administration facilitated by RebiSmart (R) could lead to high rates of adherence to a prescribed dose regimen over 36 months.