Wingless-Type MMTV Integration Site Family, Member 6 (WNT6) is a member of the Wnt family and its expression is abnormal in different human cancer cell lines. The purpose of this study was to investigate the clinical significance of WNT6 in osteosarcoma.The levels of WNT6 mRNA and protein in tissue and serum were detected through quantitative real-time polymorperase chain reaction (qRT-PCR) and Enzyme Lined Immunosorbent Assay (ELISA), respectively. Chi-square test was performed to estimate the association of WNT6 expression with clinical parameters among osteosarcoma patients. Receiver operation characteristic (ROC) curve was plotted to determine diagnostic performance of serum WNT6 in osteosarcoma. Survival analysis was performed using Kaplan-Meier method. Cox regression analysis was adopted to evaluate prognostic significance of WNT6 expression among osteosarcoma patients.Compared with the controls, WNT6 mRNA and protein levels were significantly elevated in patients with osteosarcoma (P > .05 for all). Furthermore, WNT6 upregulation showed positive correlation with patients' age (P < .001), tumor grade (P < .001) and distant metastasis (P = .001). WNT6 might be a diagnostic marker for osteosarcoma with an AUC of 0.854 combining a specificity of 88.4% and a sensitivity of 77.8%. Survival analysis result indicated that high WNT6 expression predicted poor survival (log rank test, P = .001). WNT6 might be a potential prognostic biomarker for osteosarcoma (HR = 2.227, 95%CI = 1.061-10.842, P = .027).WNT6 may be a diagnostic and prognostic marker in osteosarcoma.