Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined. We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B-cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high-dose methotrexate (HD-MTX) containing chemotherapy regimens: MPV/Ara-C (HD-MTX, procarbazine, and vincristine, followed by cytarabine [Ara-C]) (n=94, 50%), MATRix (HD-MTX, Ara-C, thiotepa, and rituximab) (n=19, 10%), HD-MTX/Ara-C (n=31, 16%), HD-MTX monotherapy (n=35, 18%) and MBVP (HD-MTX, carmustine, teniposide, prednisolone) (n=11, 6%). Cumulative median HD-MTX and Ara-C doses were 17g/m2 (range: 1-64g/m2) and 12g/m2 (0-32g/m2) respectively. Using 14g/m2 as the reference dose, the median HD-MTX relative dose intensity (HD-MTX-RDI) was 1.25 (0.27-4.57) with 84% receiving>0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD-MTX. At a median follow-up of 3.41 years (0.06-9.42), progression-free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara-C cohort (2-year PFS 74%, 2-year OS 82%; p=0.0001 and p=0.0024 respectively). On multivariate analysis, MPV/Ara-C administration and HD-MTX-RDI>0.75 were associated with longer PFS and OS. Sequential, response-adapted approaches can improve outcomes, even in older patients who are ineligible for a high-intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies.