BACKGROUND: Treatment of relapsed or refractory primary CNS lymphoma (r/r PCNSL) is difficult, particularly in patients not eligible for high dose chemotherapy with autologous stem cell transplantation (HDC-ASCT). No standard treatment has been defined for these patients yet. METHODS: We retrospectively analyzed survival, prognostic factors, hospitalization time and Karnofsky performance score (KPS) before and after treatment in 54 r/r PCNSL patients with isolated cerebral relapse or progression (n = 23 refractory, n = 31 relapsed) not eligible for HDC-ASCT, who received heterogenous salvage treatments. RESULTS: Treatments were temozolomide (+ rituximab) (n = 21), high dose methotrexate (HD-MTX)-based therapy (n = 11), whole brain radiotherapy (WBRT)/focal radiotherapy (n = 11), other systemic treatments (n = 2) and best supportive care (BSC, n = 9). Median progression free survival (PFS) and overall survival (OS) were 2.6 months (95% CI 1.0-4.2 months) and 4.8 months (95% CI 3.3-6.3 months), respectively. Eight patients survived for ≥ 3 years (13.1%, n = 3 received temozolomide, n = 3 WBRT, n = 2 HD-MTX-based treatment). Application of any salvage treatment (vs. BSC), younger age at relapse and asymptomatic (vs. symptomatic) relapse were positive prognostic factors. No significant differences in OS were found for the different salvage treatments. Median hospitalization time for treatment was 15/13 days for temozolomide (+ rituximab)/radiotherapy compared to 55 days for HD-MTX-based therapy. Median KPS in assessable patients (n = 41) was 60 (range 30-100) before treatment and 50 (range 20-90) after treatment. In patients with response to treatment (n = 16) KPS improved from 60 (range 40-90) before treatment to 70 (range 50-90) after treatment, while patients with PD (n = 25) deteriorated from 60 (range 30-100) to 40 (range 20-70). CONCLUSION: Survival for this cohort of r/r PCNSL patients with isolated cerebral relapse or progression was poor. Considering long hospital stays associated with HD-MTX-based chemotherapy and neurotoxicity associated with WBRT, temozolomide might be worth considering with a chance of prolonged survival and avoidance of long hospitalization. Novel therapeutic agents are urgently needed to improve survival in r/r PCNSL patients.