Rituximab prolongs survival in many CD20-expressing B- lymphoid malignancies. In non-Hodgkin lymphoma (NHL), a large number of clinical studies have established the 375 mg/m(2) dose of rituximab as standard. In chronic lymphocytic leukemia (CLL), response rates to single-agent rituximab at the NHL dose were low, but the use of higher doses or more frequent dosing have led to improved response rates, suggesting that a higher dose may be required. This led to the empiric decision to adopt rituximab at 500 mg/m(2) in combination with fludarabine and cyclophosphamide (FC) in phase II and III trials in CLL. The final result was the approval of rituximab at 500 mg/m(2) for treatment of CLL, in combination with FC. There is, however, preclinical evidence that full saturation of CD20 molecules may not be required to achieve chemosensitization in cancer cells, and it remains possible that the approved dose of 500 mg/m(2) is higher than what is required to achieve maximal in vivo synergy. Nevertheless, all of the randomized evidence for superiority of rituximab plus chemotherapy over chemotherapy alone comes from studies using the 500 mg/m(2) dose.