Mesenchymal stem/stromal cells (MSCs) release extracellular vesicles (EVs), which shuttle proteins to recipient cells, promoting cellular repair. We hypothesized that cardiovascular risk factors may alter the pattern of proteins packed within MSC-derived EVs. To test this, we compared the protein cargo of EVs to their parent MSCs in pigs with metabolic syndrome (MetS) and Lean controls. Porcine MSCs were harvested from abdominal fat after 16 weeks of Lean- or MetS-diet (n = 5 each), and their EVs isolated. Following liquid chromatography mass spectrometry proteomic analysis, proteins were classified based on cellular component, molecular function, and protein class. Five candidate proteins were validated by Western blot. Clustering analysis was performed to identify primary functional categories of proteins enriched in or excluded from EVs. Proteomics analysis identified 6,690 and 6,790 distinct proteins in Lean- and MetS-EVs, respectively. Differential expression analysis revealed that 146 proteins were upregulated and 273 downregulated in Lean-EVs versus Lean-MSCs, whereas 787 proteins were upregulated and 185 downregulated in MetS-EVs versus MetS-MSCs. Proteins enriched in both Lean- and MetS-EVs participate in vesicle-mediated transport and cell-to-cell communication. Proteins enriched exclusively in Lean-EVs modulate pathways related to the MSC reparative capacity, including cell proliferation, differentiation, and activation, as well as transforming growth factor-β signaling. Contrarily, proteins enriched only in MetS-EVs are linked to proinflammatory pathways, including acute inflammatory response, leukocyte transendothelial migration, and cytokine production. Coculture with MetS-EVs increased renal tubular cell inflammation. MetS alters the protein cargo of porcine MSC-derived EVs, selectively packaging specific proinflammatory signatures that may impair their ability to repair damaged tissues. Stem Cells Translational Medicine 2019;8:430-440.