Obesity and diabetes are linked to cardiometabolic diseases, however study in this field faces hardships as there are substantial prognostic heterogeneity involved. To profile the molecular mechanisms that contribute to the different responses to bariatric surgery dependent on the presence of diabetes, we sought to identify extracellular vesicular proteomic signatures of obesity with or without diabetes before or after bariatric surgery. In this study, extracellular vesicle proteins in 30 morbidly obese patients with (n = 12) or without (n = 18) diabetes were sampled before or 6 months after bariatric surgery and were compared to those in 37 healthy controls, analyzed by using the SWATH-MS analysis.