About one-third of the cases of non-Hodgkin's lymphomas occur in patients aged 60 years or more. Nevertheless, there are very few data in the literature regarding the optimal therapeutic approach for both aggressive and indolent histologies. Fludarabine-based combination regimens are an effective choice for younger patients affected by low-grade non-Hodgkin's lymphomas, but there is a lack of information about their tolerability and efficacy in older patients. We performed a phase II study to test the efficacy and safety of the combination of Fludarabine, Mitoxantrone and Dexamethasone (FND) in newly-diagnosed, chemo-naive elderly patients affected by low-grade non-Hodgkin's lymphomas with unfavorable prognostic factors. From March 1999 to March 2002, 18 patients were enrolled into the study. All the patients were evaluated for toxicity and response. Neutropenia and thrombocytopenia have been registered as the main toxicities. Thirteen (72%) patients experienced a complete response and 4 (22%) a partial response: the overall response rate was 94%. At a median follow-up of 19 months, the median time for progression-free-survival and the median survival time were not reached yet. The 2-years projected progression-free-survival and overall-survival are 52% and 67% respectively. When administered as first-line treatment to a population of elderly patients affected by high-risk, low-grade non-Hodgkin's lymphomas, FND showed a high efficacy and a good toxicity profile. Our data compare favorably to those reported for the same schedule administered both as first- or second-line therapy in younger patients.