OBJECTIVES:  To evaluate the cost-effectiveness of early versus delayed treatment with subcutaneous interferon beta-1b in clinically isolated syndrome (CIS), a first neurologic event suggestive of multiple sclerosis (MS) that precedes the majority of MS cases. METHODS:  We used a three-state (CIS, MS, death) Markov model, annual cycles, a US payer perspective, and a 50 year time horizon to compare early treatment with interferon beta-1b to delayed treatment upon progression to clinically definite MS (CDMS). Clinical data included transition probabilities from CIS to CDMS based on the BENEFIT trial which followed patients for up to 12 years. Data on expected costs and utilities after progression to CDMS were based on a recently published network meta-analysis and cost-effectiveness model of MS. In our model costs included drug treatment and utilization by Kurtzke Expanded Disability Status Scale (EDSS). Patients entered the model at age 30 when they had experienced a CIS suggestive of MS and had ≥2 clinically silent lesions on magnetic resonance imaging (MRI). We estimated costs in 2016 USD, projected life-years, and quality adjusted life years (QALYs). The primary outcome was the incremental cost-effectiveness ratio (ICER). RESULTS:  Early treatment was more expensive ($678K compared to $604K for late treatment) but associated with a greater number of QALYs (8.83 compared to 8.63 for late treatment), with an ICER of $382K per QALY. Mortality in MS and cost of treatment were the most influential model parameters, and preliminary results from a probabilistic sensitivity analysis were consistent with the main analysis. CONCLUSIONS: Early treatment of CIS may not be cost-effective from the perspective of payers in the US health system, which contrasts with economic models in other countries. Importantly, all models in this area are limited by sparse CIS-specific cost and utility data.