Hairy cell leukemia (HCL) is a rare, chronic, B-cell, lymphoproliferative disorder. Treatment has been revolutionized by the advent of interferon (IFN)-α and purine analogs (PA). First-line therapy with PA yields complete response rates of 75–100%, with many long-lasting remissions. In the event of profound neutropenia and/or infectious complications, a short sequence of IFN-α may precede PA treatment. Because of the excellent results achieved with PA therapy, the potential role of rituximab (an anti-CD20 monoclonal antibody that is highly effective against most B-cell lymphomas) in HCL has yet to be elucidated. Six HCL cases treated with rituximab are reported herein with a view to elucidating the potential role of the drug in HCL. The indications essentially consist of relapsing or refractory disease, avoiding the cumulative toxicity of PA, consolidation therapy in order to eradicate minimal residual disease, and first-line therapy for patients with contraindications to PA and IFN-α.