OBJECTIVES: To project the number and costs of relapses and escalations to second-line therapy over 2 years for subcutaneous (SC) interferon beta (IFNβ)-1a (Rebif®), intramuscular (IM) IFNβ-1a, IFNβ-1b, and glatiramer acetate (GA) in the treatment of first-line relapsing-remitting multiple sclerosis (RRMS) from the perspective of the UK National Health Service (NHS).   METHODS: A four-state (initial therapy, alternate first-line therapy, second-line therapy [natalizumab], and discontinuation) Markov model was constructed to simulate a cohort of 1,000 newly-diagnosed RRMS patients. Transition probabilities were based on real-world persistence data from the NHS and a patient treatment flow study. Risk of relapse was linearly interpolated based on 2-year data from a Cochrane Review network meta-analysis. The cost of a relapse was sourced from the literature and inflated to 2014 GBP. Drug acquisition costs were sourced from the British National Formulary. Administration costs were sourced from a NICE costing template. One-way sensitivity analyses were performed to test the robustness of the model results. RESULTS: Treatment with SC IFNβ-1a is projected to avoid 94, 7, and 7 additional relapses compared with IM IFNβ-1a, IFNβ-1b, and GA, respectively, resulting in cost savings of £279,460, £20,877, and £20,877 over 2 years in a hypothetical cohort of 1,000 newly-diagnosed RRMS patients. Treatment with SC IFNβ-1a is projected to avoid 28, 10, and 10 additional escalations to second-line therapy compared with IM IFNβ-1a, IFNβ-1b, and GA, respectively, resulting in cost savings of £685,391, £231,021, and £231,021. Results were most sensitive to each therapy’s risk of relapse at 2 years. CONCLUSIONS: Among newly-diagnosed RRMS patients, treatment with SC IFNβ-1a is projected to avoid more relapses and escalations to second-line therapy compared with IM IFNβ-1a, IFNβ-1b, and GA over 2 years. These projected cost offsets within the UK may be applicable to other payer environments.