Introduction. Angiogenesis and osteogenesis are considered two indispensable and highly coupled steps involved in successful bone repair [1, 2]. However, the nature and identities of factors that regulate the coupling process remain largely elusive. We previously found that epidermal growth factor-like protein 6 (EGFL6) is an angiogenic factor that is specifically and distinctively up-regulated during osteoblast differentiation [3]. In contrast with most currently known osteoblast-derived coupling factors, EGFL6 is highlighted with its little or low expression in other cells and tissues. This study aims to uncover the role of EGFL6 in bone repair. Methods. Primary bone marrow mesenchymal stem cells (MSCs) and MC3T3-E1 were transduced with lentiviral silencing or overexpression constructs targeting EGFL6. Bone-related markers were examined by qPCR and Western Blot (WB) assay. EGFL6 global and osteoblast-specific knockout (KO) mice were established to examine the bone phenotype under physiological conditions by using micro-CT scanning and bone histomorphometry analysis. Bone-specific type H vessels were identified using immunofluorescent staining of CD31 and Endomucin (EMCN). Mono-cortical bone defects were created in both wildtype (WT) and KO mice. Results and discussion. We found that overexpression of EGFL6 significantly enhances osteogenic capacity in vitro by augmenting bone morphogenic protein (BMP)-Smad and MAPK signalling, whereas downregulation of EGFL6 diminishes osteoblastic mineralization. Interestingly, osteoblast differentiation was not affected by the exogenous addition of EGFL6 protein, thereby indicating that EGFL6 may regulate osteoblastic function in an intracrine manner. Mice with osteoblast-specific and global knockout of EGFL6 surprisingly exhibit a normal bone phenotype under the physiological condition. However, EGFL6-deficiency leads to compromised bone repair in the bone defect model which is characterized by the decreased formation of type H vessels as well as osteoblast lineage cells. Conclusions. Taken together, our findings demonstrated that EGFL6 serves as an essential regulator to couple osteogenesis to angiogenesis during bone repair