Improving vascularization of tissue-engineered oral mucosa (TEM) is a major challenge in the field of plastic surgery. Hypoxia is a stimulator of angiogenesis through a number of mechanisms. Therefore, hypoxia is a critical parameter that can be controlled in an effort to improve angiogenesis. In the present study we studied the secretion of a number of angiogenic factors during hypoxia exposure and evaluated the effect of TEM conditioned medium on endothelial cells. TEM was constructed by seeding human oral mucosa keratinocytes and fibroblasts on acellular human donor skin. TEM was exposed to hypoxia during 6, 12, and 24 h. Cellular hypoxia was assessed by immunolocalization of the hypoxia-inducible factor-1α. Secretion of vascular endothelial growth factor, placental growth factor (PlGF), tissue inhibitors of matrix metalloproteinases-1 and -2, and the activity of matrix metalloproteinase-9 significantly increased during hypoxia exposure. Moreover, conditioned medium from hypoxic TEM strongly enhanced endothelial cell proliferation and migration. In vitro exposure of TEM to hypoxia improves its capacity to support endothelial cell proliferation and migration, which suggests that hypoxia preconditioning of TEM potentially improves angiogenic responses for in vivo implantation.