Purpose: Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytoma that tends to occur in children and young adults and has a relatively favorable prognosis. The 2021 WHO classification of tumors of the central nervous system (CNS WHO), 5th edition, rates PXAs as grade 2 and grade 3. The histological grading was based on mitotic activity (≥2.5 mitoses/mm2). This study specifically evaluates the clinical, morphological, and, especially, the molecular characteristics of grade 2 and 3 PXAs. Methods: Between 2003 and 2021, we characterized 53 tumors with histologically defined grade 2 PXA (n = 36, 68%) and grade 3 PXA (n = 17, 32%). Results: Compared with grade 2 PXA, grade 3 PXA has a deeper location and no superiority in the temporal lobe and is more likely to be accompanied by peritumoral edema. In histomorphology, epithelioid cells and necrosis were more likely to occur in grade 3 PXA. Molecular analysis found that the TERT promoter mutation was more prevalent in grade 3 PXA than in grade 2 PXA (35% vs. 3%; p = 0.0005) and all mutation sites were C228T. The cases without BRAF V600E mutation or with necrosis in grade 3 PXA had a poor prognosis (p = 0.01). Conclusion: These data define PXA as a heterogeneous astrocytoma. Grade 2 and grade 3 PXAs have different clinical and histological characteristics as well as distinct molecular profiles. TERT promoter mutations may be a significant genetic event associated with anaplastic progression. Necrosis and BRAF V600E mutation play an important role in the prognosis of grade 3 PXA.