Acute aortic dissection (AAD) and acute myocardial infarction (AMI) are both severe cardiovascular diseases that may cause sudden death. However, whether serum proteins are differentially expressed between AAD and AMI remains unclear. Here, we aimed to explore serum protein profiles between AAD and AMI patients. A total of 75 serum samples were collected, including AAD patients without AMI (n = 25), AMI patients without AAD (n = 25), and normal subjects (n=25). Protein identities and expression levels were assessed by LC-MS/MS analysis and a label-free quantitation method, respectively. After depletion of albumin and IgG, a total of 117 proteins with differential expression (fold change ≥2 or ≤−2.0, p < 0.05) were identified, of which 60 were upregulated and 57 were downregulated in AAD sera as compared to AMI sera. Bioinformatic analysis revealed that the differentially expressed serum proteins were mainly derived from exosomes and the extracellular space, and their molecular functions and biological processes were primarily involved in the activity of transporters and complements and the immune response. In addition, the serum level of Cadherin-5, an identified protein with significant regulation in AAD, was further evaluated by ELISA and the results showed that Cadherin-5 in AAD sera was higher that in AMI and healthy sera. Collectively, these findings reveal the differential serum protein profiles between AAD and AMI, which may reflect the divergent pathophysiological progression between the two cardiovascular diseases.