Background: Perinatal stem cells have prominent applications in cell therapy and regenerative medicine. Among them, human Wharton's jelly mesenchymal stem/stromal cells (hWJMSCs) and human amniotic epithelial stem cells (hAESCs) are widely used. However, little is known about the dif-ferences in the therapeutic potential of hWJMSCs and hAESCs. Methods: In this study, we reported the phenotypic differences between the two cells and provided the first systematic comparison of their therapeutic potential in terms of immunomodulation, extracellular matrix (ECM) remod-eling, angiogenesis and anti-oxidative stress by means of proteomics. Results: The results showed that the two cells had different protein expression profiles and were both promising candidates for cell therapy. hWJMSCs had a stronger angiogenic potential, while hAESCs had advantages in terms of immune tolerance and antioxidant properties. Notably, hAESCs were found to be enriched in the neurotrophin signaling pathway. Conclusions: Our study provides clues on the choice of cell type in cell therapy for different indications, which will be beneficial in advancing their further clinical translation and application.