Background and Objectives:A recent report estimated that approximately one million adults were living with multiple sclerosis (MS) in the United States (US). While MS is rarely the direct cause of death, its debilitating effects on normal body functions can result in considerable disruption to daily living and life roles including work, physical independence, mobility, social interaction, and participation in leisure activities. This study estimated the total economic burden of MS in the US in 2019.Methods:This study used a prevalence-based approach to estimate the national economic burden of MS. Claims from three sources (Medicare Current Beneficiary Survey, Medicare Standard Analytical File, and Optum de-identified Normative Health Information System) were used to obtain direct costs, while a survey was developed to collect indirect costs (e.g., labor market productivity losses, costs of paid and unpaid caregivers, home modification) from 946 patients with MS (PwMS). Direct medical costs reflected the difference in the total average annual amount paid for PwMS versus matched controls without MS. Future earnings loss due to premature death attributable to MS was calculated using Centers for Disease Control and Prevention mortality data and Medicare claims data.Results:The estimated total economic burden was $85.4 billion, with a direct medical cost of $63.3 billion and indirect and non-medical costs of $22.1 billion. Retail prescription medication (54%), clinic administered drugs (12%), medication and administration, and outpatient care (9%) were the three largest components of the direct costs. The average excess per person annual medical costs for PwMS was $65,612; at $35,154 per person, disease-modifying therapies (DMTs) accounted for the largest proportion of this cost. The cost per DMT user ranged from $57,202 to $92,719, depending on gender-age strata.The average indirect and non-medical costs were $18,542 per PwMS and $22,875 per PwMS if caregivers’ costs were included. Lost earnings due to premature death, presenteeism, and absenteeism losses were the largest indirect cost components.Discussion:MS is a very costly chronic disease, with direct costs of prescription drugs and indirect productivity loss being the significant cost drivers. Our findings suggested that the burden of MS in the US has been underestimated.