Indolent (low-grade) B-cell lymphomas are responsive to single-agent and combination chemotherapy agents, but unfortunately possess an incurable, relapsing nature. Novel agents and innovative treatment approaches need to be evaluated in these patients, with the ultimate goals of maintaining good quality of life and prolonging overall survival. Novel combinations of chemotherapeutic agents, monoclonal antibodies (both unlabeled and radiolabeled), and anti-idiotypic vaccine therapies are currently being evaluated. This article reports on the first successful clinical trial combining a chimeric anti-CD20 monoclonal antibody (rituximab; Rituxan, IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA) with standard-dose combination chemotherapy (ie, cyclophosphamide/doxorubicin/vincristine/prednisone [CHOP]) in the treatment of patients with indolent B-cell lymphoma. A 95% overall response (55%, complete remission; 40%, partial remission) rate using strict definitions for complete remission and extensive staging studies was achieved in a 40-patient intent-to-treat group. In addition, seven of seven patients with follicular histologies achieving complete remission also had clearing of BCL-2 (chromosome 14;18 translocation) positivity from blood and marrow by sensitive polymerase chain reaction assay, suggesting the eradication of subclinical minimal residual disease. Based on its single-agent efficacy, excellent toxicity profile, and ability to be successfully combined with combination chemotherapy (ie, CHOP), rituximab is currently undergoing extensive investigation in a large number of worldwide clinical trials to determine its optimal use in the treatment of CD20-positive neoplasms.