Abstract IMPORTANCE The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS) marks the entry of the diagnosis and treatment of diffuse glioma into the molecular era. The clinical implications of this landmark change in primary adult-type diffuse glioma need to be revealed. OBJECTIVE To reveal the clinical prognostic factors of adult diffuse glioma under the WHO CNS 5 classification. DESIGN, SETTING, AND PARTICIPANTS In this clinical-based prospective observational registration study, 3,308 glioma patients from 3 major neurosurgical centers were enrolled between Mar. 2005 to Jun. 2021. After excluding patients who did not meet the inclusion criteria, 1,099 primary adult-type diffuse glioma patients were eligible for inclusion in this study. Student t-test, Chi-squared test, and ANOVA were used for differential analysis. Kaplan-Meier curve and univariate and multivariate Cox regression analyses were used for survival analysis. MAIN OUTCOMES AND MEASURES Totally, 1,099 patients diagnosed with primary adult-type diffuse glioma were included in this study. The male-to-female ratio is about 1.4-1.5 to 1. The mean age at diagnosis for astrocytoma, IDH-mutant, oligodendroglioma, IDH-mutant and 1p/19q-codeleted and glioblastoma, IDH-wildtype were 39.0, 40.0, and 53.0 years, respectively. In astrocytoma, preoperative epilepsy, WHO grade, MGMT promoter methylation status, the extent of resection, and postoperative comprehensive treatment were independently associated with overall survival. For oligodendroglioma, gender, WHO grade, and extent of resection were associated with overall survival. As for glioblastoma patients, gender, age at diagnosis, preoperative KPS, preoperative epilepsy, the extent of resection, and postoperative comprehensive treatment were prognostically correlated. CONCLUSIONS AND RELEVANCE Patients in distinct molecular subtypes showed different epidemiological features and were associated with different clinical prognostic factors.