Osteosarcoma is one of the most common primary bone tumors in children and adolescents, typically presenting with poor prognosis. Recent studies have found that TSSC3 had a potential capability in suppressing the tumor development in osteosarcoma. Our purpose was to explore the role of TSSC3 in the clinical outcome of osteosarcoma patients. Firstly, we detected the expression of TSSC3 at mRNA level by quantitative real-time polymerase chain reaction (qRT-PCR). The result demonstrated that TSSC3 expression was lower in osteosarcoma patients than in healthy controls (P<0.05). Then, the relationship between TSSC3 and clinicopathological characteristics was analyzed by chi-square test which manifested that WHO grade, metastasis, and recurrence were vital influential factors on the expression of TSSC3 (P<0.05). We also estimated the association between TSSC3 and overall survival of osteosarcoma patients by Kaplan–Meier analysis as well as assessed the prognostic value of TSSC3 and clinicopathological characteristics through cox regression analysis. Patients with high TSSC3 expression were proved to live longer than those with low TSSC3 expression (log rank test, P<0.05). TSSC3 expression (P=0.032, HR=0.405, 95%CI=0.177–0.926) and metastasis (P=0.010, HR=2.849, 95%CI=1.291–6.287) were considered to be independent prognostic factors in osteosarcoma. Taken together, our findings provided preliminary evidence that the TSSC3 was a prognostic marker in osteosarcoma and this might be useful for the therapy of osteosarcoma.