We report the case of a 76-year-old man with hairy cell leukemia (HCL)-Japanese variant who underwent rituximab therapy. HCL proved refractory to treatment with pentostatin and cladribine, and the number of hairy cells in the peripheral blood continued to increase after splenectomy. The patient was treated with rituximab (375 mg/m2 intravenously weekly for 4 cycles), and hairy cells disappeared from the peripheral blood on the day after the first administration. Complete remission continued for 18 months after treatment. Although they produce high response rates in typical HCL, nucleoside analogs are associated with an inferior clinical response in HCL-Japanese variant, and repetitive administration of these agents increases the risk of serious infections. This encouraging result suggests that rituximab therapy should be considered as salvage therapy for refractory HCL-Japanese variant.