HIV-positive primary central nervous system lymphoma (PCNSL) shows complex clinical symptoms, progresses rapidly, and carries a poor prognosis. Therefore, effective therapeutic approaches along with novel detection strategies and prognostic markers are urgently needed. Although programmed death ligand 1 (PDL1) is abnormally expressed in a variety of tumors, which correlates with their biological behavior, little is known about its expression and potential role in human immunodeficiency virus (HIV)-positive PCNSL thus far. In this study, we evaluated 41 cases of HIV-positive PCNSL with immunohistochemistry for protein expression and fluorescence in situ hybridization (FISH) for the gene status of PDL1. The results showed that PDL1 protein was expressed in 92.7% (38/41) of the cases and in 53.7% (22/41) of the cases with tumor cell proportion score (TPS) > 50%. PDL1 TPS scores were found to be significantly associated with blood CD4+T-cell count (p = 0.000), lactate dehydrogenase (LDH) (p = 0.020), cerebrospinal fluid (CSF) chloride (p = 0.000), location in the lateral ventricles and basal ganglia (p = 0.019), activated B-cell (ABC)-like diffuse large B-cell lymphoma (DLBCL) (p = 0.004), necrosis area (p = 0.000), CD10 (p = 0.000), BCL6 (p = 0.003), BCL2 (p = 0.005), c-MYC (p = 0.003), Epstein-Barr encoding region (EBER) (p = 0.000), and PD1 TPS (p = 0.039). A total of 46.3% (19/41) of cases showed PDL1 gene gain. The gain of PDL1 status was positively correlated with blood CD4+T-cell count (p = 0.028), necrosis area (p = 0.011), and BCL6 (p = 0.050). It was discovered that the PDL1 gene gain was correlated with protein overexpression (p = 0.004). Survival analyses showed that PDL1 gain was significantly associated with worse survival (p = 0.024). Multivariate analyses demonstrated that PDL1 gain was an independent predictive factor for poor prognosis (p = 0.043). Despite the limited cohort size, these findings suggest that PDL1 gain could be considered a potential biomarker for prognosis in the context of PD1/PDL1 therapy.