Fludarabine (FLU) is a fluorinated purine analogue with a promising antineoplastic activity in lymphoproliferative disorders. In this study, we evaluated the efficacy of FLU in 12 previously treated (primary refractory and refractory relapse) patients with Waldenstrom's macroglobulinemia. All patients were treated at a dosage of 25 mg/m2 per day for 5 consecutive days for a total of six courses. Of the 12 patients, 5 (41%) achieved partial response (PR), and the remaining 7 showed no benefit from the treatment. An increased response rate was obtained in the 4 primary refractory patients in which 2 PR were documented. Treatment was well-tolerated and there were no Fludarabine-related fatalities. With a mean follow-up of 10 months, only 1 PR patient has relapsed. Fludarabine is an interesting new salvage agent effective against recurrent/resistant Waldenstrom's macroglobulinemia and should be evaluated in further studies in untreated patients with Fludarabine in monochemotherapy or in combination with other active modalities.