Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare non-Hodgkin's lymphoma (NHL) confined to the brain, spine, eyes and leptomeninges [1], [2]. PCNSL comprises about 5% of newly diagnosed primary central nervous system (CNS) tumors and 1% of all NHL. Data of PCNSL from nationwide population-based studies from Western Europe, North America, and Asia converge to range the annual incidence rate between 0.3 and 0.5/100,000 persons. Based on the surveillance, epidemiology, and end results (SEER) registry database the incidence rate in the United States has grown continuously from 1975 to 2017 with a five-fold increase, consistent with several studies in other countries [3], [4], [5], [6], [7], [8], [9]. However, incidence of PCNSL varied greatly by age group, with patients aged over 60 representing the population growing the most [7], [10], [11], [12], [13] and becoming today the large majority of patients, with a median age of 68 years [14]. The reasons for this increase remain unelucidated. Immunodeficiency is the main risk factor, but since the dramatic decrease in the number of AIDS PCNSL patients due to the development of highly active antiretroviral therapy (HAART), PCNSL in immunocompromised patients has become rare, mainly observed in patients given immunosupressive agents. In the present review, we will focus on PCNSL in immunocompetent patients.