OBJECTIVES: To evaluate the cost-effectiveness of 44 mcg subcutaneous interferon beta-1a (scIFNβ1a) in patients with multiple sclerosis (MS) with Kurtzke Expanded Disability Status Scale (EDSS) score >3.5–5.0.  METHODS: The analysis was performed from a US payer perspective. The time horizon of the analysis was 2 years. The decision analytic model was populated with real-world inputs and related assumptions, as well as pivotal placebo-controlled clinical trial data for 44 mcg scIFNβ1a 3 times a week (PRISMS Study). Clinical inputs were obtained for the overall study population as well as a subpopulation of patients with Kurtzke EDSS score >3.5–5.0. Disease-modifying drug (DMD) cost was based on 2014 wholesale average cost with consideration of patient copayment in the base case. Sensitivity analyses were conducted on key input variables to assess their impact on cost per relapse avoided. RESULTS: Model results showed that the mean number of relapses avoided with 44 mcg scIFNβ1a in patients with EDSS >3.5–5.0 was 1.21 per patient over 2 years. The mean number of relapses avoided for the overall study population was 0.74 per patient over 2 years. The average cost-effectiveness of 44 mcg scIFNβ1a was estimated to be $107,861 per relapse avoided for the EDSS >3.5–5.0 cohort. The average cost-effectiveness for the overall study population was estimated to be $181,208 per relapse avoided. Sensitivity analyses showed that results were robust to changes in key input parameters such as DMD costs, the number of relapses in untreated patients, the relative risk reduction in clinical relapse rates, the rate of adherence, and the average cost of relapse. CONCLUSIONS: Based on model results, the average cost-effectiveness of 44 mcg scIFNβ1a was favorable for both the overall study population and the EDSS >3.5–5.0 cohort.