Infiltration of inflammatory cells and vascular remodeling are hallmark observations during pulmonary fibrosis. The roles of inflammatory cells as well as the significance of Vascular Endothelial Growth Factor (VEGF) in this context have been debated controversially. It is still not clear whether angiogenesis is a prerequisite for the fibrotic changes in the lung, a necessary compensatory mechanism or just a bystander without any causative effect. To test the role of myeloid cell-derived VEGF in the development of pulmonary fibrosis, we created an in vivo, cell lineage-specific targeted deletion of VEGF, via crosses of the loxP-flanked VEGF allele to the lysozyme M promoter-driven Cre recombinase (LysMCre/VEGF+f/+f). In a model of radiation-induced pulmonary fibrosis as well as in bleomycin-induced fibrosis, deletion of VEGF in myeloid cells resulted in decreased pulmonary VEGF levels and reduced blood vessel formation but significantly aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of Hypoxia-inducible factors (HIF's) and Wnt/b-catenin signaling. These observations argue that the process of angiogenesis driven by myeloid cell-derived VEGF is crucial for adequate tissue repair and prevention of fibrotic damage.