<p> Background: Relapsed/refractory primary central nervous system lymphoma (r/r - PCNSL) is associated with a dismal prognosis. The Zanubrutinib, Lenalidomide, and Rituximab regimen has been shown to be effective and well - tolerated in treating relapsed/refractory PCNSL, particularly among patients with the MYD88 and CD79B Mutations (MCD). Nevertheless, there is a dearth of published data on the “real - world” application of this regimen, especially in patients with central nervous system (CNS) involvement. Methods and Materials: This study included 16 patients diagnosed with relapsed/refractory primary central nervous system lymphoma. These patients had received at least one prior line of treatment and were administered the Zanubrutinib, Lenalidomide, and Rituximab therapy within a compassionate - use program from January 2020 to September 2023. Results: Upon completion of the induction therapy, 12 (75%) patients achieved complete remission (CR), and 1 (6%) patient achieved partial remission (PR). One patient (6%) had stable disease (SD), while 3 patients (19%) had progressive disease (PD), resulting in an overall response rate (ORR) of 81%. At a median follow - up of 416 days (ranging from 59 to 877 days), most of the responses were maintained. Six (46%) patients had radiologically confirmed PD. The 2 - year progression - free survival (PFS) rate was 48.6%, and the 2 - year overall survival (OS) rate was 72.3%. In the subgroup analysis, participants with the MCD subtype exhibited significantly better PFS (<i>p</i> = 0.005). Conclusions: The Zanubrutinib, Lenalidomide, and Rituximab regimen appears to have promising efficacy and acceptable safety in treating relapsed/refractory PCNSL, particularly for patients with the MCD subtype.</p>