BACKGROUND: Natalizumab (NAT) is an established disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, its use involves complex decision-making, often leading to initial use of lower efficacy therapies. Recently, the first biosimilar NAT was approved, enabling competitive pricing. This study assessed the societal implications of initiating NAT in various scenarios through a cost-consequence analysis. METHODS: A 10-year Markov model based on the Expanded Disability Status Scale (EDSS) was employed, with 11 health states, annual cycles, and half-cycle correction. The cohort had an initial age of 36 years and 70% females. NAT was compared to common initial therapies (glatiramer acetate, teriflunomide, dimethyl fumarate, and fingolimod). Scenarios included continuous use, early (after 1 year), and delayed (5 years) switch to NAT. Baseline characteristics and probabilities for clinical and economic outcomes were derived from clinical trial data, published literature, and other available sources. RESULTS: Continuous NAT use resulted in the highest time spent on low EDSS levels, fewer relapses, reduced years of life lost due to disability, and a higher employment rate over a 10-year period. Switching to NAT after 1 year yielded outcomes similar to continuous NAT use. Despite higher DMT costs, disease management costs, including indirect costs and non-DMT direct medical costs, were lower in continuous use and early switch to NAT. Late switching resulted in outcomes most comparable to continuous use of the initial DMT. CONCLUSION: Continuous and early switch to NAT resulted in better clinical outcomes and lower societal economic burden compared to delayed NAT initiation, indicating potential long-term cost savings.