Background Although the paracrine efects of mesenchymal stem/stromal cells (MSCs) have been recognized as crucial mediators of their regenerative efects on tissue repair, the potential of MSC secretomes as efective substi tutes for cellular therapies remains underexplored. Methods In this study, we compared MSCs from the human dermis (DSCs) and adipose tissue (ASCs) with their secretomes regarding their efcacy for skin wound healing using a translationally relevant murine model. Results Proteomic analysis revealed that while there was a substantial overlap in protein composition between DSC and ASC secretomes, specifc proteins associated with wound healing and angiogenesis were diferentially expressed. Despite a similar angiogenic potential in vivo, DSC and ASC secretomes were found to be less efective than cells in accelerating wound closure and promoting tissue remodeling. Conclusions Overall, secretome-treated groups showed intermediary results between cells- and control-treated (empty scafold) groups. These fndings highlight that although secretomes possess therapeutic potential, their efcacy might be limited compared to cellular therapies. This study contributes to the growing understanding of MSC secretomes, emphasizes the need for further protocol optimization, and ofers insights into their potential applica tions in regenerative medicine.