The aim of the study was to investigate the therapeutic activity of Fludarabine in patients with low-grade non-Hodgkin's lymphoma (LG-NHL) no longer responding to standard treatment. In this Phase II study patients were treated with Fludarabine 25 mg/m2 intravenously daily for 5 days repeated at 28-day intervals. Twenty-two patients with LG-NHL, no longer responding to standard treatment, were entered in the study. Among twenty-one evaluable patients, seven had a complete and six a partial response. The median time to treatment failure and survival time are 4.6 months and >28.0 months, respectively. The most important toxicity was hemogram suppression, which was usually manageable but occasionally severe. Fludarabine is not only an active agent with definite therapeutic value in patients with treatment-resistant LG-NHL, but effective and well tolerated in patients no longer responding to standard treatment.