Aims Previous thorax irradiation promotes metastatic spread of tumor cells to the lung. We hypothesized that vascular damage facilitates lung metastasis after thorax irradiation and that therapeutically applied multipotent mesenchymal stromal cells (MSCs) with reported repair activity may prevent these adverse effects of ionizing radiation by protecting lung endothelia from radiation-induced damage. Results Previous whole thorax irradiation (WTI) with 15Gy significantly enhanced seeding and metastatic growth of tumor cells in the lung. WTI was further associated with endothelial cell damage, senescence of lung epithelial cells and up-regulation of invasion- and inflammation-promoting soluble factors, e.g. endothelial matrix metalloproteinase 2 (Mmp2), its activator Mmp14, the co-factor tissue inhibitor of metalloproteinases 2 (Timp2), chemokine (C-C motif) ligand 2 (Ccl2), and urokinase-type plasminogen activator (Plau/uPA), and recruitment of CD11b+CD11c- myelomonocytic cells. Inhibition of Mmp2 counteracted radiation-induced vascular dysfunction without preventing increased metastasis. In contrast, therapy with bone marrow or aorta-derived MSCs within two weeks post-irradiation antagonized radiation-induced damage to resident cells as well as the resulting secretome-changes and abrogated the metastasis-promoting effects of WTI. Innovation Therapy with MSCs protects lungs from radiation-induced injury and reduces the risk of lung metastasis. MSC-mediated inhibition of Mmp2 mediates their protective effects at the vasculature. Further local and systemic effects such as inhibition of radiation-induced senescence of bronchial epithelial cells and associated secretion of immunomodulatory factors may participate in the inhibitory effect of MSCs on lung metastasis. Conclusion MSC-therapy is a promising strategy to prevent radiation-induced lung injury and the resulting increased risk of metastasis.