Multiple Sclerosis (MS) is the second cause of paraplegia among young adults, after all types of CNS traumatic lesions. In its most frequent relapsing-remitting form, the severity of the disease course is very heterogeneous, and its reliable evaluation remains a key issue for clinicians. Myeloid-Derived sSuppressor Cells (MDSCs) are immature myeloid cells that suppress the inflammatory response, a phenomenon related to the resolution or recovery of the clinical symptoms associated with experimental autoimmune encephalomyelitis (EAE), the most common model for MS. Here, we establish the severity index as a new parameter for the clinical assessment in EAE. It is derived from the relationship between the maximal clinical score and the time elapsed since disease onset. Moreover, we relate this new index with several histopathological hallmarks in EAE and with the peripheral content of MDSCs. Based on this new parameter, we show that the splenic MDSC content is related to the evolution of the clinical course of EAE, ranging from mild to severe. Indeed, when the severity index indicates a severe disease course, EAE mice display more intense lymphocyte infiltration, demyelination and axonal damage. A direct correlation was drawn between the MDSC population in the peripheral immune system, and the preservation of myelin and axons, which was also correlated with T cell apoptosis within the CNS (being these cells the main target for MDSC suppression). The data presented clearly indicated that the severity index is a suitable tool to analyze disease severity in EAE. Moreover, our data suggest a clear relationship between circulating MDSC enrichment and disease outcome, opening new perspectives for the future targeting of this population as an indicator of MS severity.