Mantle cell lymphoma is an aggressive B cell tumor, with a median survival of approximately 3 years, despite treatment. While intensive therapy may be curative in some patients, the median age at diagnosis is in the 60’s, and such therapy is not always feasible. We developed a regimen of fludarabine, mitoxantrone and rituximab, comprised of fludarabine, 25 mg/m2, IV on days 1–3; mitoxantrone, 10mg/m2, IV on day 1, every 28 days for 6 cycles, along with rituximab, 375 mg/m2 given on day 1, of cycles 2 through 6, and then given alone for 3 weekly doses as cycle 7. To date, 14 male and 7 female patients with a median age of 60 years (range 41–87) have been accrued. Five patients (24 %) relapsed from prior systemic chemotherapy including stem cell transplantation in 1. All but 1 patient had either stage III (n=2) or stage IV disease (n=20). Sites of extranodal disease included bone marrow in 15 (71%), pleural effusions in 5 (24 %), and GI tract involvement in 3 (14 %) patients. Eight patients (38 %) had an intermediate or high IPI score. B symptoms were present in 7. On pathologic assessment, no patient had blastoid morphology. Cyclin D1 was expressed in 19 of 21 tissues tested. Treatment has been well tolerated; the most common side effect was transient grade 3 or 4 neutropenia reported in 17 (81 %) patients; transient grade 3 or 4 thrombocytopenia in 3 patients; and anemia observed in 6 patients. No grade 3 or 4 non-hematologic toxicity has been reported. Of 20 evaluable patients, complete remissions (CR) have been documented in 18 (90 %). The median duration of complete remission is 17.4 months (range 1.1–29.9). Thirteen patients have relapsed after 1.1 to 29.9 months in CR. All 20 of the evaluable patients remain alive after a median follow-up of 16.4+ mos (range 1.0–39.6+). Combination therapy with fludarabine, mitoxantrone, and rituxan is a well tolerated regimen and is highly active in patients with both newly diagnosed and relapsed mantle cell lymphoma. While relapse is seen in the majority, the regimen is capable of inducing CR in 90 % and can be used safely in elderly patients and those who have relapsed or are not eligible for stem cell transplant.