Central nervous system (CNS) relapse is an infrequent but severe complication for DLBCL patients, associated with poor prognosis. Intravenous prophylaxis with high-dose methotrexate has shown promising results but is rarely feasible in elderly and/or nephropathic patients. A 83 years old woman with CNS relapse occurred 6 months after chemoimmunotherapy. The patient was defined ineligible for radiotherapy (RT) and started oral Temozolomide 250mg daily for 5 consecutive days without any improvement after 1st cycle. We administered lenalidomide 25mg daily for 21 days every 28 days together with temozolomide 250mg daily for 5 days every 28 days. The patient experienced a rapid improvement of general and cognitive conditions; Gadolinium-enhanced brain MRI showed a wide reduction of neoplastic tissue. The patients maintained good clinical conditions with mild treatment toxicity until the end of the 6th cycle, when brain MRI showed disease progression and the patient died 1 month later. We suggest lenalidomide could be a feasible option for CNS relapse in elderly DLBCL patients and it could be associated in future studies with other cytotoxic agents such as temozolomide.