Updated project metadata. Using plasma samples collected from pre-diabetic non-obese diabetic (NOD) mice (an experimental model of T1D) we performed parallel analysis of whole plasma samples and plasma-derived extracellular vesicle (EV) fractions using mass spectrometry (MS). Whole plasma samples were depleted of abundant proteins (albumin, transferrin and IgG) and subjected to high resolution isoelectric focusing (HiRIEF) LC-MS and relative quantification by TMT 10-plex. EV-enriched samples were analyzed by standard LC-MS/MS. Our results suggest that parallel profiling of EV-enriched plasma fractions and whole plasma samples increases the overall proteome depth and facilitates the discovery of tissue-enriched proteins in plasma.