The clinicopathological features of HIV-related primary central nervous system lymphoma (PCNSL) and immunocompetent primary central nervous system lymphoma (IC-PCNSL) were found to be distinct. Thirty-seven patients with HIV-related PCNSL and thirty patients with IC-PCNSL were included in our study. Hematoxylin & eosin (HE) staining, immunohistochemical detection using CD10, MUM1, CD20, Bcl-2, Bcl-6, p53, C-MYC, Ki67, methyltransferase like factor 3 (METTL3) antibodies and Epstein-Barr encoding region (EBER) in situ hybridization were performed. All of the patients were classified as the diffuse large B-cell lymphoma (DLBCL) histological type. Patients with HIV-related PCNSL were younger and more likely to be male, with elevated lactate dehydrogenase (LDH) and low sugar content in cerebrospinal fluid (CSF) compared to patients with IC-PCNSL.The positive rates of METTL3, Bcl-2, p53 and EBER were significantly higher in HIV-related PCNSL patients than in IC-PCNSL patients. Furthermore, we also found that the expression of METTL3 was lower in germinal centre B-cell (GCB)-like DLBCL (n = 7) than in non-GCB like DLBCL (n = 30) in HIV-related PCNSL (P = 0.030); however, in IC-PCNSL patients, the expression of METTL3 was not significantly different between GCB-like DLBCL and non-GCB-like DLBCL (P = 0.670). Although the manifestations are similar in PCNSL patients with and without HIV, HIV-related PCNSL differs from IC-PCNSL in terms of pathological characteristics including METTL3, Bcl-2, p53 and EBER. We therefore suggest that the pathogenesis of HIV-related PCNSL and IC-PCNSL may differ according to host immune status.