Temporal bone squamous cell carcinoma (SCC) accounts for less than 2% of all head and neck tumors. Its biologic parameters should be investigated because clinicopathologic factors are often inaccurate for the purposes of its prognosis. CD105 is a proliferation-associated protein expressed in angiogenic endothelial cells and a potential prognostic indicator for several solid malignancies. The present study is the first to investigate the prognostic role of CD105 expression in temporal bone SCC. Retrospective clinicopathologic investigation. Tertiary referral centers. Twenty consecutive operable patients with temporal bone SCC. CD105 immunohistochemical expression in primary temporal bone SCCs was assessed using image analysis. CD105 expression was correlated with conventional clinicopathologic and prognostic parameters. Using the revised Pittsburgh staging system, T and stage correlated with local recurrence rate (p = 0.0001 and p = 0.0001, respectively) and disease-free survival (p = 0.043 and p = 0.018, respectively). The recurrence rate was significantly higher (p = 0.038) and the disease-free survival shorter in patients with CD105 expression of 9.44% or higher (p = 0.038) than in cases where it was less than 9.44%. The crude carcinoma recurrence risk ratio of was 5.9 times higher for patients whose CD105 expression was 9.44% or higher. CD105 expression in activated endothelial cells of temporal bone SCC can be considered potentially useful for detecting patients at a higher risk of local disease recurrence after treatment. Further investigations are needed to ascertain the feasibility of incorporating targeted anti-CD105 therapy in multimodality or multitarget strategies for temporal bone SCC treatment.