e21516 Background: Osteosarcoma (OS) is a highly malignant tumor with a peak incidence in adolescents and young adults. Patient's prognosis is limited to clinical parameters whereas molecular markers of tumor aggression are yet to be identified. Vitamin D (Vit D) has been postulated as a novel therapeutic option for a variety of malignancies such as breast and prostatic carcinomas. The biologic effect of vitamins is mainly mediated through receptors. Vit D receptors (VDRs) are members of the steroid hormone superfamily and are ubiquitous in a various tissues including bone. Upon activation by its ligand, VDR combines with retinoid receptor (RXR) forming a heterodimer initiating a cascade of cellular events. How Vit D induces its antineoplastic activity in OS remains to be elucidated. Methods: Immunohistochemical analysis for VDR, RXR, Ki-67, and bcl-2 was performed on 87 OS specimens to evaluate differentiation, proliferation and apoptosis. Clinical data including site of the primary tumor, presence or absence of metastasis, therapeutic regimens, and outcome were recorded. Results: The mean age of OS patients is 25.7 years (range 7–68). Fifty-four patients were <30 years. Thirty-five OSs were conventional, 17 chondroblastic, 6 giant cell, 6 fibroblastic, 6 mixed, 3 telangiectatic, and 2 epithelioid variants. Twelve of the 87 samples were metastatic. All metastatic OSs were high grade, located in the lungs with a mean age of 25 years (range 7–52). The majority of the OSs expressed VDR (74/87, 85%) and RXR (72/78, 92%). Proliferative activity varied between tumors types with highest Ki-67 percentage noticed in conventional variant (29%), followed by chondroblastic variant (16%). Metastatic tumors consistently had the highest proliferative activity as compared to primary tumors (35%). None of the tumors studied was immunoreactive for bcl-2. Conclusions: Our results demonstrate that VDR and RXR are expressed on most OSs. A significant relationship exists between tumor histologic types and proliferative activity. Metastatic OSs appears to have a significantly higher level of proliferative activity as compared to primary tumors. These results would establish a foundation for elucidating mechanisms by which Vit D induces its antineoplastic activity in OS. No significant financial relationships to disclose.