Abstract Background De-escalating natalizumab (NTZ) to interferon beta 1b (IFN B 1B) is a possible treatment option in multiple sclerosis (MS) patients interrupting NTZ because of increased risk of progressive multifocal leukoencephalopathy (PML). The aim of this study was to evaluate satisfaction and adherence to treatment, behavioral and fatigue changes in patients switched to IFN B 1B compared to continued NTZ treatment. Methods A 1 year, prospective, randomized, rater-blinded, parallel-group study. Nineteen relapsing remitting (RR) MS patients, randomly assigned to undergo either NTZ (n = 10) or IFN B 1B (n = 9) treatment, who had previously received NTZ for at least 12 months with disease stability and fearing or at risk for PML were included. Patients underwent behavioral and treatment assessments at baseline, after 24-week and 1 year follow-up. Behavioral assessment included measures of cognition, fatigue and quality of life. Treatment assessment included measures of satisfaction, persistence and adherence to treatment. Clinical-radiological disease activity and safety were also assessed. Results Baseline characteristics of patients were similar between groups except for Euro Quality Visual Analogue Scale, being higher in the NTZ group (p = 0.04). Within-group comparisons at the three time points, as well as interaction analysis of treatment effect over time did not show any statistically significant differences in behavioral or treatment assessments, but a coherent trend favoring NTZ over IFN B 1B. Conclusions De-escalating NTZ to IFN B 1B is feasible and associated with overall good patient related outcome and persistently stable behavioral measures.