Primary central nervous system lymphoma (PCNSL) is a rare and aggressive malignancy with limited treatment options and presents significant therapeutic challenges. Although high-dose methotrexate (HD-MTX)-based immunochemotherapy, followed by autologous stem cell transplantation (ASCT), improves outcomes in patients with PCNSL, in clinical practice, ASCT eligibility is frequently restricted by medical unsuitability, patient choice, and socioeconomic factors. In this retrospective study, we evaluated 12 newly diagnosed PCNSL patients who were treated with a combination of rituximab, HD-MTX, and lenalidomide (R2-MTX) without ASCT. With a median follow-up of 43.0 months, the R2-MTX regimen demonstrated superior clinical efficacy, achieving an overall response rate (ORR) of 91.7% (95% CI: 61.5-99.8%), with a complete response (CR) rate of 66.7% at the end of induction therapy. The median overall survival (OS) was not reached, while the median progression-free survival (PFS) was 62 months (range: 6-64 months). The estimated 2- and 5-year OS rates were 91.7% (95% CI: 76.0-100%) and 70.7% (95% CI: 52.1-99.3%), respectively, with corresponding PFS rates of 66.7% (95% CI: 50.1-93.3%) and 57.1% (95% CI: 34.5-83.7%), respectively. Treatment-related toxicities were manageable, with no grade ≥ 3 adverse events observed. The most common adverse effect was neutropenia (46.2%). Notably, patients with CARD11 mutations experienced a high rate of early relapse despite lenalidomide treatment. In conclusion, the R2-MTX regimen showed encouraging efficacy and a manageable safety profile in a small cohort of newly diagnosed PCNSL patients unsuitable for ASCT. These preliminary findings suggest that R2-MTX may be a promising therapeutic alternative, but validation in larger, prospective multicenter studies is warranted.© 2025. The Author(s).