This dataset contains proteomic profiles of extracellular vesicles (EVs) isolated from human multiple sclerosis (MS) white matter tissue, alongside the corresponding tissue proteome. The aim of this study is to characterize the protein cargo of MS-derived EVs compared to bulk tissue and to identify molecular features linked to MS pathology. Proteins were labeled using TMTpro 18-plex reagents, fractionated by basic pH reversed-phase LC, and analyzed by Orbitrap Fusion Lumos mass spectrometry.