18520 Background: Primary CNS lymphoma (PCNSL) is an aggressive primary brain tumor, cranial irradiation alone rarely result in long term disease control or prolonged survival. We analyzed our data for the impact of adding high dose methotrexate (HDMTX) prior to whole brain irradiation (WBI). Methods: All patients with PCNSL diagnosed and managed during 1991–2004 were identified from Oncology Data Unit. Patient’s characteristics, prognostic factors, details of treatment and outcome were reviewed. Sixty-two patients were identified, 10 were excluded (4 had WBI < 40 Gy and 6 had no treatment). Radiation alone was considered curative with a dose ≥ 40 Gy. Combined modality therapy included 3–4 cycles of HDMTX (3gm/m2) followed by WBI Results: 52 patients were analyzed for outcome. 36 had WBI, dose ≥40 Gy, 16 received 3–4 cycle of HDMTX followed by WBI (chemo-radiotherapy (CRT)). Median age was 48.2 years; 42 years in CRT group, 51 years in WBI. Patients characteristics were comparable between two groups except for higher multifocal tumor in CRT group (92% vs. x22%, p=0.029). Median follow is 12.83±6.4 months. Results are shown in Table . HR for event is 0.64 (95% CI was 0.52–0.98) and for death 0.58 (95% CI was 0.48–0.92), both in favor of CRT. Univariate regression analysis using one-way analyses of variance (ANOVA) and multivariate Cox regression analysis for prognostic factors including age (< 60 vs. ≥60), ECOG PS (0–2 vs. 3–4), extent of surgery (biopsy vs. debulking), solitary vs mutifocal tumor and dose of radiation therapy (< 50Gy vs. ≥50Gy) failed to identify any prognostic factor. Conclusions: This retrospective comparison supports other phase II trials results that high dose methotrexate followed by WBI in PCNSL improves outcome. [Table: see text] No significant financial relationships to disclose.