Multiple sclerosis (MS) is a highly heterogeneous immune-mediated demyelinating disease. Myelin restoration is essential to prevent disability progression in MS patients. However, remyelinating therapies are failing in clinical trials, in part, due to the lack of biomarkers that classify the differing endogenous regenerative capacities of enrolled patients. In the experimental autoimmune encephalomyelitis (EAE) MS model, circulating monocytic myeloid-derived suppressor cells (M-MDSCs) are associated to milder disease courses, better recovery and less degree of tissue damage. Here, we show that disease severity affects the gradient of oligodendrocyte precursor cells (OPCs) present in mixed active-inactive lesions of MS patients, along with a positive correlation between M-MDSC density and OPC abundance. EAE disease severity negatively influences the density of total and newly generated OPCs found associated to the demyelinated lesions. In addition, disease severity also impacts the abundance of newly generated oligodendrocytes throughout the EAE disease course. Interestingly, circulating M-MDSCs at EAE onset and peak of the disease are directly associated to a higher density of newly generated oligodendrocytes in the demyelinated lesions. Our results set the basis for further studies on M-MDSCs as a promising new biomarker that identify a CNS prone to new oligodendrocyte generation in response to an inflammatory insult.