Vascular endothelial growth factor-C (VEGF-C) and its receptor, vascular endothelial growth factor receptor-3 (VEGFR-3), have been implicated as important factors in the formation of lymphatic vessels, but its role in osteosarcomas has not yet been fully investigated. This study aims to define the expression of VEGF-C and VEGFR-3 in primary and metastatic osteosarcomas and their relationship to various clinicopathologic parameters. Thirty-three primary osteosarcomas and two pulmonary metastatic samples were immunostained for VEGF-C and VEGFR-3. In addition, VEGF-C and vascular endothelial growth factor-D (VEGF-D) mRNA expression levels in three different human osteosarcoma cell lines and control fibroblasts were evaluated by real-time quantitative polymerase chain reaction (PCR). Both VEGF-C and VEGFR-3 were expressed mainly in the cytoplasm of the tumor cells. Of the 35 patients with osteosarcoma, 16 patients (45.7%) showed strong positive reaction with VEGF-C. Four cases (11.4%) were negative, and 15 cases (42.9%) showed weak immunoreactivity. For VEGFR-3, 12 patients (34.3%) showed strong positive reaction. Fifteen cases (42.9%) were negative, and eight cases (22.8%) showed weak immunoreactivity. A significant, positive correlation (Rs=0.42, p=0.01) was found between the expression of VEGF-C and VEGFR-3 in osteosarcomas. The expression of VEGF-C was significantly associated with the osteoblastic subtype and high histologic grade in osteosarcomas. However, the expression of VEGF-C showed no significant correlation with the presence of metastasis. Expression of VEGFR-3 was not related to any clinicopathologic features analyzed. Two of the three osteosarcoma cell lines tested showed amplification of VEGF-C mRNA compared with control cells. No amplification of VEGF-D was noted in these cell lines. Our data suggest that VEGF-C and its receptor are expressed in osteosarcomas. Although the level of VEGF-C was high, it does not seem to have a direct influence on tumor metastasis in osteosarcomas.