A retrospective analysis to compare the treatment outcomes of two regimens with different doses of methotrexate (MTX). Seventy-two patients, newly diagnosed with primary central nervous system lymphoma between 1995 and 2006, were included. All patients were treated with one of the two different MTX regimens depending on when the diagnosis was made. Thirty-six patients diagnosed between 1995 and 2002 were treated with 1 g/m² of intravenous MTX (HD-MTX 1 g/m², cohort 1). The other 36 patients, diagnosed between 2003 and 2006, received 3.5 g/m² of intravenous MTX (HD-MTX 3.5 g/m², cohort 2). The median age was 47 years (range, 17-78 years) and 42 patients (58.3%) were male. The median overall survival (OS) and progression-free survival (PFS) of all patients was 90.3 and 52.9 months, respectively. Although OS and PFS was not statistically different between the two cohorts, cohort 2 achieved higher complete response/unconfirmed complete response rates than cohort 1 at an evaluation conducted between completion of intravenous MTX therapy and the initiation of radiotherapy (52.8% vs. 16.7%, respectively; p = 0.005). Furthermore, there were no deaths within 6 months of MTX therapy for the cohort 2, whereas there were eight deaths by 6-months for cohort 1 (p = 0.003). Even though cohort 2 failed to show superior survival outcomes compared with cohort 1 after sequential brain radiotherapy and intravenous cytarabine, the higher early CR/CRu rate of cohort 2 compared with cohort 1 might indicate that a high dose of MTX is desirable.