OBJECTIVES: Epiphyseal cartilage is a barrier to osteosarcoma invasion, however the mechanisms behind this resistance remain unclear. The aim of this study was to examine the chronological and spatial patterns of osteosarcoma growth and invasion of local tissue structures including epiphyseal cartilage. METHODS: We used an in vivomouse model of osteosarcoma to histologically examine tumors at different stages of disease progression. We compared the pattern of osteosarcoma penetration of epiphyseal cartilage with the expression pattern of two potent mediators of angiogenesis; proangiogenic vascular endothelial growth factor (VEGF) and antiangiogenic pigment epithelium-derived factor (PEDF). RESULTS: Epiphyseal cartilage remained intact across its entire length in all sections examined, despite increasing tumor size as well as intra- and extraosseous destruction. In the most advanced cases, only the proangiogenic lowermost layers of the hypertrophic zone of the growth plate were eroded. This corresponded with the growth plate layers which highly expressed the angiogenic factor VEGF. In contrast, the resting, proliferative and upper hypertrophic layers were resistant to osteosarcoma invasion in all cases. This corresponded to the layers with the highest expression of the potent antiangiogenic factor PEDF. CONCLUSION: Epiphyseal cartilage is resistant to local invasion by osteosarcoma. The balance of angiogenesis, influenced by pro- and antiangiogenic factors, is likely to play an important role in this resistance.