The role of myeloid cells in the pathogenesis of MS is determined by the polarization they acquire after activation, and mediated by release of extracellular vesicles (MVs). We assessed the effects of treatments for MS on activation and polarization of myeloid cells. MVs levels and markers of polarization of myeloid cells have been assessed at baseline and up to 6 months after the start of a MS treatment. Patients had higher levels of MVs than controls, and these increased significantly over 6 months under natalizumab. Interferon β-1a significantly decreased M1 pro-inflammatory marker IL1β and upregulated Trem2, a receptor important for debris clearance; both interferon β-1a and fingolimod decreased pro-inflammatory marker IL6. Current treatments for MS significantly modulate myeloid cells activity.