Alterations in molecular elements derived from the CXC chemokine receptor 4 (CXCR4)/stromal-derived factor 1 (SDF-1) cytokine system have been found to strongly correlate with neoplastic progression leading to metastasis in a number of tumors, including osteosarcoma. Excluding hematologic malignancies, chondrosarcoma of bone is the most common primary malignant tumor of bone in adults in the United States. Like osteosarcoma, chondrosarcoma preferentially metastasizes to lung, bone, and very rarely to regional lymph nodes. However, the role of the signal pathway(s) driving neoplastic progression in chondrosarcoma has not yet been clearly elucidated. To test whether CXCR4 was detectable in chondrosarcoma and whether CXCR4 expression levels correlated with chondrosarcoma grade. Twenty-two chondrosarcoma samples banked at our institution between 2001 and 2006 were retrieved for study. By using invasive ductal carcinoma of the breast and osteosarcoma as the positive controls, immunohistochemistry was performed on paraffin-embedded tissue sections and the intensity of the tumor cells was analyzed by morphometric techniques. All chondrosarcoma cases (22 of 22) were immunoreactive for CXCR4. However, the staining intensity of the CXCR4 between the low- and high-grade groups was significantly different. There was a higher staining intensity in high-grade chondrosarcoma cells (P < .001). CXCR4 is expressed in chondrosarcomas. CXCR4 expression levels were higher in high-grade chondrosarcoma cells than in low-grade specimens. A larger number of cases will be required to confirm these results and expand the observation, but preliminary data would argue for CXCR4 immunohistochemistry as a potential marker for biologic aggressiveness in chondrosarcoma of bone.