This study examines the establishment an animal model of bone invasion by oral squamous cell carcinoma to clarify the mechanisms of osteoclast-mediated bone invasion. C(3)H/HeN mice were inoculated with SCCVII cells into the masseter region. At the end of week 3, all surviving mice were sacrificed and analyzed by three-dimensional imaging using micro-computed tomography, histopathological observation using Hematoxylin-Eosin staining and Tartrate-Resistant Acid Phosphatase staining, and confirmation of mRNA expression of the osteoclast-related cytokines IL-6, TNF-alpha, and PTHrP. SCCVII cells rapidly multiplied in the masseter muscle of the mice. Bone invasion was evident only in the SCCVII transplanted group on micro-computed tomography. The histopathologic findings obtained with H-E and TRAP staining indicated that the tumor cells in the mandible of all animals of the SCCVII transplanted group exhibited funicular invasion and presented a serrated pattern of bone resorption. The mRNA expression of IL-6, PTHrP, and TNF-alpha increased as the control decreased. SCCVII cells were highly invasive into mandibular bone in C(3)H/HeN mice. This model was similar to the invasion of human oral cancer into maxillary and mandibular bone. Our mandibular invasion model may provide a powerful new modality for the diagnosis and treatment of oral cancer with bone invasion.