Estimating direct healthcare costs of patients with multiple sclerosis (MS) and identifying risk factors of high costs including relapse are important drivers of public health decision making in France.This is a longitudinal retrospective study based on patient charts (qualified registry of MS in Lorraine (ReLSEP)) and claims data (from the main compulsory health insurance and national hospital database estimated monthly. All patients with MS not deceased or lost to follow-up reported in the registry in 2013-2014 were included. Outpatient costs were those paid to the healthcare provider and inpatient costs were those related to national cost estimates. Mean total costs per patient by disease severity were estimated monthly, accounting for MS evolution over the study period. Costs of MS relapse were estimated using a general linear model.A total of 4373 patients were identified in the ReLSEP registry, and 2166 of these patients were included in the study. Among those, outpatient claims were available for 1366 and 627 were hospitalized at least once. The average annual direct costs for patients with MS were estimated to be €12,296 in 2014. Furthermore, ambulatory costs represented 87.8% out of those costs and were mainly driven by medications (60.6%) and paramedic visits (11.2%). Monthly direct costs were higher in patients with severe disease (€1249 for EDSS 7-9) compared to those with mild or moderate disease (€992 for EDSS 0-3; €953 for EDSS 4-6) (p < 0,006). Interestingly, drug costs were higher in patients with mild disease, whereas costs related to paramedical care, medical devices, and transportation were higher in those with severe MS. The unit cost of relapse was estimated between €1681 and €2193.Costs were mainly driven by medications and highly related to disease severity. Relapse cost was the main contributor to total cost.