PURPOSE: To investigate the alteration of glymphatic activity in high-grade glioma (HGG) using the diffusion tensor image (DTI) analysis along perivascular spaces (ALPS) method and assess its prognostic performance. METHODS: Data of HGG and volunteer were retrieved from The Cancer Imaging Archive and Consortium for Reliability and Reproducibility databases, respectively. Image features including multicenter, cystic change, tumor location, midline structure, lateral ventricle compression, and nerve fiber involvement were evaluated for HGG. The ALPS-index was calculated, and the difference of ALPS-index (D_ALPS), was defined to represent the difference of bilateral ALPS-index. RESULTS: In total, 236 HGG and 61 volunteers were included. The ALPS-index of the tumor-side hemisphere was larger than that of the normal-side, but it was smaller than that of volunteers. The ALPS-index of the normal-side showed a decreasing trend for HGG cases presenting a compressed lateral ventricle, deviated midline structure, and peritumor edema-involved association and projection fibers, but increased in gross total resection. The D_ALPS increased for isocitrate dehydrogenase mutation. The normal-side ALPS-index negatively correlated with edema and tumor volume. The D_ALPS positively correlated with edema volume. Univariable and multivariable Cox analysis revealed smaller D_ALPS as independent factors for poor prognosis. Survival analysis showed that high D_ALPS corresponded to longer survival times compared to low D_ALPS. CONCLUSIONS: The glymphatic activity in HGG individuals is lower compared with that of healthy volunteers, with a potential compensation in the tumor side. Many clinical-radiological characteristics affect the glymphatic activity. The defined D_ALPS shows potential as an independent prognostic factor in HGG.