Background: Lenalidomide is an immunomodulator agent that exhibits efficacy in multiple myeloma and haematological malignancies including refractory/relapsed diffuse large B-cell (DLBC) systemic lymphoma (Witzig et al, Ann Oncol 2011). Methods: Retrospective review of PCNSL patients treated with lenalidomide at the Pitié-Salpêtrière hospital. Inclusion criteria were: (1) immunocompetent status (2) pathologically proven diagnosis of DLBC-PCNSL, (3) recurrent or refractory disease after at least two prior chemotherapy treatments, including intravenous high-dose methotrexate and cytarabine based regimens, (4) lenalidomide administered orally, at a dose of 25 mg/day on days 1-21 of a 28-days cycle. MRI scans were performed monthly. Response was evaluated according to the IPCG criteria. Results: Between June 2011 and March 2013, 6 patients (4 women and 2 men) met the inclusion criteria. Lenalidomide was given as 3rd line in 4 patients, as 4th line in 1 and 5th line in 1. Median age was 73.5 years (range 64-78) and median Karnofsky Performance Status was 60 (range 40-70). Two patients achieved complete response (CR). Patient 1 received a total of 9 monthly cycles of lenalidomide without any steroids and is still in remission after a follow-up of 18 months from the start of the treatment. Patient 2 achieved a CR and was off-steroids at the time of CR, but relapsed during the third cycle and died after 14 weeks. Patient 3 achieved a partial response after one cycle but died suddenly during the second cycle. Patients 4, 5, and 6 progressed and died 2, 5, and 6 months respectively after the start of lenalidomide. One of them who suffered from an oculo-cerebral relapse demonstrated a partial ocular response while progressing in the brain. Apart from the sudden death of unknown cause, the treatment was well tolerated. None of the patients experienced any grade III or IV toxicity. Conclusions: These results suggest that lenalidomide exhibits activity in heavily pre-treated PCNSL and is well tolerated in elderly patients. Lenalidomide efficacy on PCNSL needs to be evaluated prospectively, alone or in association with other cytotoxic agents. A phase II trial combining rituximab and lenalidomide for recurrent PCNSL is on-going in France (NCT01956695).