Background: Primary CNS Lymphoma (PCNSL) is an aggressive form of diffuse large B-cell lymphoma (DLBCL). Lenalidomide is an immunomodulatory agent which has shown activity in R/R non-CNS DLBCL non-germinal center subtype (GCB) and R/R CNS DLBCL (primary and secondary). The ideal dosing, timing of lenalidomide as consolidation therapy, and it’s role in maintenance therapy remain unclear. Methods: Here we describe three elderly patients with R/R PCNSL who were treated with lenalidomide. All patients had a pathological diagnosis of PCNSL (subtypes: 2 GCB, 1 non-GCB), immunocompetent status, R/R status despite at least 2 previous therapies including intravenous methotrexate and rituximab. One of the patients had also failed autologous stem cell transplant (ASCT). Lenalidomide was administered orally, 25mg/day on days 1-21 of a 28-day cycle. Results: Median age was 68 (range 65-71). Median KPS was 70 (range 60-70). Patient 1 achieved complete response (CR) after cycle 4, 2 additional maintenance cycles (20mg; reduced for Grade 3-4 Thrombocytopenia), and is in remission after 9 months. Patient 2 achieved partial response (PR) after cycle 1, CR after cycle 8, and 2 additional maintenance cycles; dose reduced at cycle 6 (20mg) for Grade 3-4 Neutropenia, and is in remission after 12 months. Patient 3 achieved PR after cycle 1, mixed response after cycle 2, and died 15 weeks after start of treatment; of note, patient was also on rituximab. Molecular and immunologic correlates are pending and will be presented with the abstract. Conclusions: This case series shows lenalidomide has single agent activity in heavily pre-treated R/R PCNSL. All three patients had clinical and radiographic response to treatment, and two patients remain progression-free at 9 and 12 month follow-up. Hematologic toxicities occurred at the higher dose, however even at reduced dose, lenalidomide was effective in maintaining remission. In elderly patients, using lenalidomide at relapse and deferring neurotoxic treatment options may have a role in preserving good performance status. Further prospective studies are warranted to determine the efficacy and optimal dose of lenalidomide in patients with newly diagnosed and R/R PCNSL.