Background Osteosarcoma is aggressive and prognostic biomarkers are important to predict the outcomes of surgery and chemotherapy. Here, we investigated the potential of transferrin receptor-1 (TfR1) and vascular endothelial growth factor (VEGF) as prognostic markers of osteosarcoma. Methods TfR1 and VEGF in osteosarcoma samples from a cohort of 53 osteosarcoma patients were detected by immunohistochemistry analysis. The correlation of TfR1 and VEGF levels with clinicopathological parameters was analyzed by Pearson chi-square and Spearman-rho tests. Overall patient survival was analyzed by the Kaplan-Meier method. Results We found that TfR1 and VEGF expression levels were low in 20.8% and 18.9%; modest in 35.8% and 35.8%; and high in 43.4% and 45.3% of osteosarcoma patients, respectively. TfR1 and VEGF expression was significantly correlated to histologic grade, Enneking stage, and distant metastasis. TfR1 expression was significantly correlated to VEGF expression and both TfR1 expression and VEGF expression were correlated to shorter overall survival. Conclusions TfR1 and VEGF are potential prognostic factors for osteosarcoma.