This study compares the immune responses of patients undergoing coronary artery bypass grafting (CABG) via on-pump and off-pump methods. On-pump CABG induced a more significant immune response, with notable increases in extracellular vesicles (EVs) derived from platelets, endothelial cells, and B-cells. Off-pump surgery was associated with milder changes in cytokine and EV profiles. Findings highlight EVs’ role in regulating postoperative inflammation and suggest a potential mechanism for immune modulation.