Ezrin, a cytoskeleton linker protein, has been reported to be involved in the metastasis of solid tumors in animal models and patients in small clinical studies. We analyzed the relationship between immunohistochemical expression of ezrin and the prognosis of osteosarcoma. We retrospectively identified 64 patients with Stage IIB osteosarcomas between 1995 and 2000. Tissue microarrays were constructed from incisional biopsy specimens and immunohistochemical staining was performed. Ezrin expression and other clinicopathologic variables such as age, gender, pathologic subtype, tumor size and location, and histologic response were compared with outcomes. The minimum followup was 12 months (mean, 78.2 months; range, 12-137 months). Twenty-three of 64 patients (35.9%) showed late distant metastasis; 33 of 64 patients (51.6%) showed expression of ezrin, and of these 33 patients, 22 (66.7%) had distant metastasis develop. Multivariate analysis revealed histologic response to preoperative chemotherapy and expression of ezrin predicted disease-free survival. Expression of ezrin in osteosarcoma biopsy specimens is promising as a marker to predict outcome in patients with osteosarcoma.