Background <p>New-onset postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) is a major complication and the precise mechanism remains unclear. EVs have become a special intercellular information transmission system secreted from different cells. The present study aimed to identify differentially expressed proteins (DEPs) of the plasma exosomes (Extracellular Vesicles, EVs) from patients with POAF after CABG and explored the pathogenesis of POAF.</p> Methods <p>Label-free quantitative LC–MS/MS proteomics analyses were performed to find changes in protein levels proteomic alterations in plasma EVs of patients with POAF (<i>n</i> = 6) after CABG and sinus rhythm (SR, <i>n</i> = 6). The DEPs screened by bioinformatics analysis were validated by parallel reaction monitoring (PRM) quantitative analysis from a new set of plasma samples (POAF <i>n</i> = 9; SR <i>n</i> = 9).</p> Results <p>Exosomal proteomics identified 51 significant DEPs including 29 up-regulated and 22 down-regulated proteins in POAF group compared to the SR control. Bioinformatics analysis showed that the DEPs were significantly enriched in cysteine and methionine metabolism, Toll-like receptor signaling pathway, AGE-RAGE signaling pathway in diabetic complications and Diabetic cardiomyopathy. The PRM reconfirmed that serum amyloid P-component and Collagen alpha-2(I) chain were significantly down-regulated in POAF group.</p> Conclusions <p>This study provides a new insight into the exploration of the pathogenesis of POAF. Abnormally expressed SAP and Collagen alpha-2(I) chain correlate to POAF and might be further explored for their role in the occurrence of POAF. These two proteins in the plasma EVs may be developed as biomarkers for future diagnosis and treatment of POAF in the clinical setting.</p>