This study was designed to report the pharmacokinetic behavior of Rituximab in patients affected with different diseases and treated with different schedules of administration. A low tumor burden was a common feature of all patients (N=48) included in our study, whereas the timing of Rituximab administration varied from weekly (groups 1, 2, 3) to monthly (group 4). Group 1 included patients with follicular lymphoma treated with 4 weekly doses of Rituximab after first-line chemotherapy with CHOP. At the start of Rituximab, patients were in partial or complete clinical response but showed persistence of disease at molecular level (bcl-2-positive) in bone marrow and/or peripheral blood. Patients in group 2 had autoimmune disorders and Rituximab was given to act on B-cells, interfering with their production of autoantibodies. In patients with amyloidosis (group 3), Rituximab was given to kill progenitor B-cells of the small clone terminating in amyloid-producing plasma cells. In groups 2 and 3, the target of monoclonal antibody was a population of small B cells, which make an intrinsic feature of the diseases. Group 4 included patients with relapsed or refractory follicular and mantle cell lymphoma who underwent a salvage program of immunochemotherapy, purging in vivo and autotransplant: the first of the six planned doses of Rituximab was administered after a debulking phase with a third-generation regimen, such as VACOP-B. An enzyme-linked immunoassay (ELISA) developed and validated in our laboratory was used for the pharmacokinetic study. Rituximab disposition was characterized by a 2-exponential decay, with a long elimination half-life of approximately 3 weeks (range, 248-859 hours). The total systemic clearance ranged between 3.1 and 11.9 mL/hr/m. After 4 weekly infusions, Rituximab concentration was approximately 2.5 microg/mL, which is approximately 85% of the steady-state level. Steady-state plasma concentrations of Rituximab were reached after 6 to 8 weekly infusions. The adopted pharmacokinetic model (2-compartment open model) seems to provide the best fit of Rituximab disposition both during and after treatment, even when different schedules of drug administration are used. Because several studies reported an association between response and serum Rituximab concentrations, a treatment based on a pharmacokinetic model may be useful for predicting the desired drug concentration.