Background <p>Advances in the availability and regimen optimization of highly effective disease-modifying treatments (DMTs) for relapsing–remitting multiple sclerosis (RRMS) have led to questions about their comparative worth.</p> Objectives <p>This study evaluates the costs and effects of natalizumab versus other highly effective DMTs and the impact, in terms of times and costs, of the new subcutaneous natalizumab formulation versus the intravenous formulation in patients with RRMS in Italy.</p> Methods <p>This is a cost-consequence analysis from the Italian national health service and societal perspectives. A Markov model was developed to assess clinical and cost outcomes related to disease and DMTs. The model simulated two scenarios: one comparing natalizumab extended-dose regimen and ofatumumab and ocrelizumab, focusing on efficacy outcomes and costs, and one comparing intravenous and subcutaneous natalizumab with a focus on administration resource consumption, times, and costs. Model input data came from the literature.</p> Results <p>DMTs had similar clinical and social outcomes: natalizumab slightly reduced disease progression, increased quality-adjusted life-years, and reduced the impact on days of productivity loss and informal care. Natalizumab also resulted in statistically significant 5-year cost reductions compared with ocrelizumab and ofatumumab. Subcutaneous natalizumab improved resource consumption compared with intravenous natalizumab, saving the time of healthcare professionals, patients, and caregivers and reducing administration costs. The subcutaneous formulation was associated with statistically significant total direct and indirect cost reductions at 5 years.</p> Conclusion <p> 6-week dosing regimen&#xa0;of natalizumab showed a slight improvement of clinical and social outcomes and a statistically significant cost reduction compared with ocrelizumab and ofatumumab over a 5-year simulation. Moreover, subcutaneous administration reduced administration times and costs.</p>