The transdifferentiation of cancer cells into other types of cells in several types of tissues or organs has been studied. However, whether human osteosarcoma MNNG/HOS cells can transdifferentiate into other types of cells has seldom been reported. Meanwhile, the mechanism of tumor angiogenesis is still disputed, and whether MNNG/HOS cells participate in angiogenesis in osteosarcoma remains unknown. In the present study, the investigation was divided into two parts: in vitro and in vivo. In vitro, we cultivated MNNG/HOS cells under hypoxic conditions for 4 days and found that they typically showed a characteristic 'flagstone' appearance as cultured vascular endothelial cells (VECs). MNNG/HOS cells that were cultivated on Matrigel under hypoxic conditions gradually formed tubular-like structures. Furthermore, when cultured under hypoxic conditions for 4 days, MNNG/HOS cells also transcribed and expressed several molecular markers of VECs (CD31, CD34 and vWF). In vivo, MNNG/HOS cells (1x106 cells) were cultivated under hypoxic conditions and subcutaneously injected into nude mice; the mice were sacrificed 49 days after inoculation. Immunohistochemical staining with anti-human CD31 antibody showed evidence of tumor angiogenesis in human osteosarcoma MNNG/HOS cells. The results demonstrated that MNNG/HOS cells can transdifferentiate into vascular endothelial cell-like cells in vitro and in vivo.