Plasma-derived extracellular vesicles (EVs) have been extensively described as putative biomarkers in different diseases. More precisely, increased levels of EVs subpopulations are well-known to associate with obesity. The goal of this study was to identify EVs-derived biomarkers in plasma from obese patients in order to predict the development of pathological events associated with obesity. The study was performed combining two different proteomic approaches (2D-DIGE and label-free LC-MS/MS). Samples were obtained from 22 obese patients, with no associated comorbidities, and their lean-matched controls. EVs were isolated following a serial ultracentrifugation protocol. We detected 22 and 23 different regulated protein features from 2D-DIGE and label free LC-MS/MS respectively. Most of the differentially regulated proteins identified were involved in the coagulation and complement cascade. Interestingly, there was a clear up-regulation of complement C3, complement C4 and fibrinogen in obese patients following both approaches, which correlates with a pro-inflammatory and prothrombotic state of those individuals. On the other hand, we showed a down-regulation of adiponectin leading to an increased risk of suffering cardiovascular diseases. Our results suggest the relevance of considering plasma-derived-EVs proteins as a source of potential biomarkers for the development of atherothrombotic events in obesity.