Optimal treatment for splenic marginal zone lymphoma (MZL) is not clearly established. Splenectomy has been proposed as the treatment of choice in patients with cytopenias and/or symptoms caused by an enlarged spleen. Splenic MZL, which expresses the CD20 antigen on tumor cell surfaces, is a disease entity candidate to treatment with anti-CD20 monoclonal antibodies. We employed an immunochemotherapy regimen with rituximab/cyclophosphamide/vincristine in 3 patients with splenic MZL who had only a partial response following CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) or CHOP-like therapy. The immunochemotherapy regimen was well tolerated and all patients exhibited complete remission. To our knowledge, this is the first report of splenic MZL showing response to a combination of rituximab with chemotherapy.