Osteosarcoma (OS) is the most common primary solid malignant bone tumor, and its metastasis is a prominent cause of high mortality in patients. In this study, a prognosis risk signature was constructed based on metastasis-associated genes. Four microarrays datasets with clinical information were downloaded from Gene Expression Omnibus, and 256 metastasis-associated genes were identified by limma package. Further, a protein-protein interaction network was constructed, and survival analysis was performed using data from the Therapeutically Applicable Research to Generate Effective Treatments data matrix, identifying 19 genes correlated with prognosis. Six genes were selected by the least absolute shrinkage and selection operator regression for multivariate cox analysis. Finally, a three-gene (MYC, CPE, and LY86) risk signature was constructed, and datasets GSE21257 and GSE16091 were used to validate the prediction efficiency of the signature. The survival times of low-and highrisk groups were significantly different in the training set and validation set.Additionally, gene set enrichment analysis revealed that the genes in the signature may affect the cell cycle, gap junctions, and interleukin-6 production. Therefore, the three-gene survival risk signature could potentially predict the prognosis of patients with OS. Further, proteins encoded by CPE and LY86 may provide novel insights into the prediction of OS prognosis and therapeutic targets.differentially expressed genes, metastasis, osteosarcoma, risk signature, survival analysis 1 | INTRODUCTION Osteosarcoma (OS), characterized by malignant mesenchymal cells producing an osteoid matrix and fibrillary stroma, is the most common osseous aggressive cancer in children and juveniles and commonly arises at the terminus of the long bones, including distal femurs, proximal tibias, and proximal humor. 1 According to the National Cancer Institute Surveillance, Epidemiology, and End Results program, the frequency of OS has increased by 0.3% per year over the last decade. 2 With the intensification of chemotherapeutic regimens, the 5-year survival rate of OS patients without metastasis has been improved to 60%-70%. 3 By contrast, the survival rate is only 0%-30% in patients with OS with metastasis, 4 indicating that OS metastasis is associated poor longterm prognosis. However, metastasis-associated molecules Yi Shi and Ronghan He contributed equally to this work.