Background: Primary central nervous system lymphoma (PCNSL) is a rare cancer accounting for less than 3% of primary brain and central nervous system (CNS) tumors. Tissues involved include the brain parenchyma, leptomeninges, eyes, and spinal cord. High-dose methotrexate (HD-MTX) is the gold standard for newly diagnosed PCNSL. However, the efficacy of stereotactic radiosurgery (SRS) instead of whole brain radiotherapy following HD-MTX for PCNSL is unclear. The purpose of this study is to determine the effectiveness of HD-MTX in combination with SRS in the treatment of PCNSL. Methods: This is a retrospective, observational cohort study evaluating the treatment of histologically confirmed PCNSL with HD-MTX as a single agent in a dose of 3.5 g/ m 2 (control) and treatment with MTX plus SRS. Strict inclusion and exclusion criteria were employed. Primary outcomes were measured by overall survival. Secondary outcomes were assessed by the tumor's responsiveness to treatment and reduction in size as noted on imaging, the Karnofsky Performance Status (KPS), the activities of daily living (ADL) and mini-mental state examination (MMSE). Results: Between January 2008 and January 2013, 68 cases were evaluated. Included in this evaluation were 42 chemotherapy and 26 chemotherapy, plus SRS. The follow-up period was 24 to 50 months (mean: 32.8 months). There were no statistically significant differences in patient demographics or histology diagnosis. Patients were treated with SRS doses ranging from 11 Gy to 16 Gy (mean: 13 Gy). The median survival rate from initial diagnosis was 28.6 months in the chemotherapy group and 48.6 in the chemotherapy, plus SRS, group (p-value: 0.0051). No significant side effects related to SRS were observed. During follow-up period, the good ADL preservation was achieved for 16 months from SRS. Patients with KPS >90 at SRS demonstrated longer ADL preservation (36 months from SRS). No significant difference in MMSE between two groups were found. Conclusions: SRS in combination with high-dose methotrexate provided better prognosis and not worse neurocognition state. This noninvasive treatment modality should be considered as an option for patients with PCNSL, but should be validated in a large patient population. Legal entity responsible for the study: