In subjects with obesity, we found that PCSK9 may impact on the release of EVs-derived from atherosclerotic components (i.e., platelets, endothelium, monocytes/macrophages, and neutrophils) as well as on EVs-derived miRNA linked to atherosclerosis (hsa-miR-362, hsa-miR-150, hsa-miR-1244, hsa-miR-520b-3p, and hsa-miR-638) and their related targeted genes (e.g., LDLR, TLR4, and ESR1). This evidence concerns the gene TLR4 and obesity due to melanocortin 4 receptor deficiency.