<h3>Purpose/Objective(s)</h3> Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, and the IDH-wildtype GBM, accounting for about 90% of GBM cases, is characterized by poor prognosis and response to the standard chemoradiotherapy. B7-H3, a B7-family immunoregulatory protein, has been reported to correlate with poor survival in various solid tumors and to enhance radioresistance in colorectal cancer. However, the effect of B7-H3 on chemoradioresistance and prognosis in IDH-wildtype GBM remains unexplored. Therefore, this study analyzes the potential of B7-H3 expression as a predictive biomarker for chemoradiosensitivity and a prognostic factor in IDH-wildtype GBM. <h3>Materials/Methods</h3> 65 patients histopathologically diagnosed with IDH-wildtype GBM undergoing standard chemoradiotherapy (Stupp Protocol) at a single institution from 2015 to 2019 were involved in this retrospective study. Patients were divided into the chemoradioresistant group and chemoradiosensitive group based on the short-term treatment outcome. Patient tumor tissue samples were subjected to immunohistochemistry for B7-H3 expression. Receiver operating characteristic (ROC) analysis was exploited to estimate the diagnostic value. Kaplan-Meier curves, the log-rank test and Cox proportional hazard model were used to test for the prognostic association of B7-H3 expression <h3>Results</h3> B7-H3 expression in patients resistant to chemoradiotherapy (n=18) was significantly higher than that in patients sensitive to chemoradiotherapy (n=47) (p=0.048, t-test). ROC curves showed that the area under the curve (AUC) for B7-H3 expression was 0.778 (95% CI = 0.670-0.926; p=0.001). Patients with high B7-H3 expression demonstrated significantly shorter median progression-free survival (PFS) and median overall survival (OS) than patients with low B7-H3 expression (median PFS = 10 vs. 21 months, p=0.047; median OS = 17 vs. 31 months, p=0.023). univariable Cox proportional hazard model displayed an increased risk of death for patients with high B7-H3 expression (hazard ratio=5.926; 95% CI=1.669-21.044; p=0.006). <h3>Conclusion</h3> Our results suggest that B7-H3 expression might serve as a potential biomarker for chemoradiosensitivity prediction in IDH-wildtype GBM. Moreover, the data demonstrate B7-H3 expression as a prognostic factor candidate for IDH-wildtype GBM. This study implies previously unrecognized B7-H3 contribution to chemoradioresistance, encouraging future studies to explore further the mechanisms behind.