Abstract: Splenic lymphoma with villous lymphocytes (SLVL) is an indolent lymphoproliferative disorder of mature B lymphocytes. Splenectomy is primarily recommended for treating this disease, and splenic irradiation or alkylating agents may be effective; however, frequent recurrence is observed after these therapies. We report here an unusual case of SLVL in which the degree of splenomegaly and the serum IgM level increased rapidly. Although the effects of splenic irradiation and combination chemotherapy were both unsatisfactory and transient, complete remission lasting for more than 15 months was achieved after two courses of treatment with low-dose fludarabine (15 mg m−2 daily for 3 d). The present case indicates that treatment with fludarabine is effective for SLVL and recommended as the first-line therapy for elderly patients and those with an aggressive form of the disease.