Treatment with single-agent chemotherapy or rituximab (R) is safe and moderately effective for patients with Waldenström macroglobulinemia (WM). We analyzed the efficacy and toxicity of fludarabine (F)-combinations. Twenty-nine treatment episodes were administered to 27 patients, including FC (F 25 mg/m(2) days 1-3, cyclophosphamide [C] 250 mg/m(2) days 1-3; n = 7), FCR (FC + R 375 mg/m(2) day 1; n = 18), FM (F + mitoxantrone [M] 10 mg/m(2) day 1; n = 3), and FR (n = 1). Patient characteristics were median age 57 years (36-89), 83% male, 10 previously untreated (34%). In total, 123 cycles were administered, a median of four (2-6) per patient. Grade ≥ 3 neutropenia and infections complicated 28% and 3% of cycles, respectively. Responses were achieved in 26 cases (90%), one complete, 23 partial, and two minor. The median progression-free survival was 43.1 months, and at a median follow-up of 66.5 months the actuarial 5- and 10-year overall survival-rates were 88% and 75%, respectively. All 10 previously untreated patients responded (one CR, nine PR), and were alive at a median follow-up of 50 (6-106) months. Three heavily pretreated patients subsequently developed AML/MDS (one fatal) at 56, 61, and 91 months post F-based treatment. F-combination therapy is highly active in WM, both untreated and alkylator-refractory. However, a possible contribution to the cumulative risk of treatment-related MDS/AML requires ongoing monitoring.