We report on the use of fludarabine in four patients with splenic lymphoma with villous lymphocytes (SLVL). All four had relapsed after, or failed to respond to, recommended first-line therapies. In each case fludarabine resulted in a complete clinico-haematological response with minimal toxicity, which, in the two patients with long-term follow-up, proved durable. Fludarabine is effective in the treatment of SLVL and should be considered as both a first-line therapeutic option as well as salvage therapy in this condition.