OBJECTIVES: To use health economic modeling techniques to quantify and compare the clinical and economic outcomes associated with the use of subcutaneous interferon beta-1a (scIFNβ1a) vs. intramuscular interferon beta-1a (imIFNβ1a) over 2 years in the management of relapsing forms of multiple sclerosis (MS) from a US healthcare payer perspective.  METHODS: The 2-year decision analytic model was populated with IMS LifeLink Plus prevalence and treatment data, and clinical data from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study, a direct head-to-head comparison of 44 mcg scIFNβ1a three times a week vs. 30 mcg imIFNβ1a once a week. Relapse data from 16-month results were extrapolated for the 2-year model. Disease-modifying drug (DMD) costs were based on 2014 wholesale average cost with consideration of patient copayment in the base case. The model was created with the ability to customize the rate of copayment as well as to incorporate contractual discounts, if desired. One-way sensitivity analyses were conducted on key parameters using alternate plausible values, including the rates of real-world DMD adherence.  RESULTS: For a hypothetical health plan with 1 million members, it is estimated that 911 patients with MS would be treated with DMDs. More relapses were avoided with scIFNβ1a over 2 years (979) than with imIFNβ1a over 2 years (778). The average cost-effectiveness of 44 mcg scIFNβ1a was lower (more favourable) than the average cost-effectiveness of 30 mcg imIFNβ1a ($123,854 vs. $148,749 per relapse avoided). Sensitivity analyses around model input values showed the model was robust and cost-effectiveness results were consistent. The model results are most sensitive to drug cost.  CONCLUSIONS: Cost-effectiveness assessment may facilitate the decision-making process in selecting MS treatments. Using the highest-quality clinical data (Level 1, head-to-head study, EVIDENCE), the cost-effectiveness of 44 mcg scIFNβ1a was shown to be favourable compared with 30 mcg imIFNβ1a