BackgroundWe aimed to establish an osteosarcoma prognosis prediction model based on a signature of endoplasmic reticulum stress-related genes.MethodsDifferentially expressed genes (DEGs) between osteosarcoma with and without metastasis from The Cancer Genome Atlas (TCGA) database were mapped to ERS genes retrieved from Gene Set Enrichment Analysis to select endoplasmic reticulum stress-related DEGs. Subsequently, we constructed a risk score model based on survival-related endoplasmic reticulum stress DEGs and a nomogram of independent survival prognostic factors. Based on the median risk score, we stratified the samples into high- and low-risk groups. The ability of the model was assessed by Kaplan–Meier, receiver operating characteristic curve, and functional analyses. Additionally, the expression of the identified prognostic endoplasmic reticulum stress-related DEGs was verified using real-time quantitative PCR (RT-qPCR).ResultsIn total, 41 endoplasmic reticulum stress-related DEGs were identified in patients with osteosarcoma with metastasis. A risk score model consisting of six prognostic endoplasmic reticulum stress-related DEGs (ATP2A3, ERMP1, FBXO6, ITPR1, NFE2L2, andUSP13) was established, and the Kaplan–Meier and receiver operating characteristic curves validated their performance in the training and validation datasets. Age, tumor metastasis, and the risk score model were demonstrated to be independent prognostic clinical factors for osteosarcoma and were used to establish a nomogram survival model. The nomogram model showed similar performance of one, three, and five year-survival rate to the actual survival rates. Nine immune cell types in the high-risk group were found to be significantly different from those in the low-risk group. These survival-related genes were significantly enriched in nine Kyoto Encyclopedia of Genes and Genomes pathways, including cell adhesion molecule cascades, and chemokine signaling pathways. Further, RT-qPCR results demonstrated that the consistency rate of bioinformatics analysis was approximately 83.33%, suggesting the relatively high reliability of the bioinformatics analysis.ConclusionWe established an osteosarcoma prediction model based on six prognostic endoplasmic reticulum stress-related DEGs that could be helpful in directing personalized treatment.