This prospective study of 111 patients with severe obesity assessed whether “non-conventional” biomarkers, including vaso-inflammatory markers, gut hormones, and extracellular vesicle (EV) surface profiles, may better foreshadow cardiovascular-metabolic outcomes after bariatric surgery (BS) than standard clinical and biochemical parameters. Samples were obtained at baseline, at 1 year (T12) and at 3 years (T36) after BS. At T36, body weight fell from a median 111 kg to 77 kg, with a 30% BMI reduction. Consistently, all the traditional cardiovascular risk indicators improved, with a lower prevalence of hypertension, dyslipidaemia, and type 2 diabetes and lower need for the respective therapies. A complete post-surgical outcome was defined in case of no residual CV diseases without medications, and a BMI less than 30 kg/sqm at follow-up, whereas a poor outcome was assigned when no improvement was detected in CV risk profile or number of medications, and/or the BMI at follow-up was equal or higher than 30 kg/sqm. Baseline conventional parameters alone could not discriminate outcome classes, while this objective was achieved combining non-conventional biomarkers. Their post-surgical combined trajectories were associated to the improvement of cardiovascular profile, with a decrease in serum amyloid A, IL-6, TNF-a, and insulin, an increase in GLP-1, ghrelin, PYY, and bile acids, alongside to the decreased number of circulating vesicles and the reduced expression of EV-antigens related to inflammatory cells, dysfunctional endothelium, and activated platelets. Notably, a lower baseline expression of several EV-carried antigens characterized patients who later achieved a complete outcome, consistently with a reduction in the metabolic and vascular inflammatory burden after BS. Multivariable models adjusted for age, sex, childhood weight, and follow-up duration showed that EV concentration (tetraspanins CD9, CD63, and CD81) and specific EV antigens (CD4, CD11c, CD20, CD29, CD31, CD40, CD41b, CD42a, CD44, CD62P, CD69, and CD209) were associated with a worse CV outcome. Receiver-operating curves for these EV markers yielded AUCs of 0.693–0.816, supporting their potential to enhance baseline risk stratification beyond conventional factors. Strengths of the study include the multimodal biomarker panel, repeated paired comparisons up to 3 years after BS, and a clinically scalable EV-immunocapture workflow. Limitations include missing patients at T36 with possible selection bias, mixed surgical procedures (Roux-en-Y-bypass, sleeve gastrectomy, one-anastomosis gastric bypass), and the need for inter-laboratory standardization and external validation, especially before translating EV signatures into a routine pre-/post-operative work-up, or applying them with incretin-based therapies, now reshaping obesity care. Overall, integrating EV profiling with gut hormones and inflammatory markers appears to capture a residual risk which is not reflected by traditional metrics and could guide a more personalized follow-up strategy in surgically treated obesity.