The prognosis of patients with diffuse large B-cell lymphoma with central nervous system (CNS) involvement is still poor. We performed a pilot study to establish treatment for patients who had refractory or recurrent CNS involvement without employing high-dose chemotherapy or stem cell support. Eight patients with diffuse large B-cell lymphoma and CNS disease after first-line chemotherapy were enrolled. They were treated with MIND-E therapy (ranimustine, ifosfamide, procarbazine, dexamethasone, and etoposide) every 4 weeks. Three patients achieved complete remission, two patients achieved partial remission, and three patients did not respond. One patient received an autologous peripheral stem cell transplant after MIND-E therapy. Three patients are still alive. In conclusion, MIND-E therapy was effective for CNS disease in patients with B-cell lymphoma who were judged to be poor candidates for intensive chemotherapy. Its toxicity was tolerable. A prospective study should be done to confirm the efficacy of this regimen.