The objective of this multiinstitutional study was to evaluate the safety and efficacy of rituximab at standard four weekly doses in patients with recurrent indolent lymphoma. Thirty-eight patients entered into this study, 63% had follicular lymphoma and 61% had an IPI score of 2 or more. Median disease duration was 3 yr, median number of prior treatments was three, and 66% of patients responded to the immediate past treatment with a median remission duration of 3 mo. A total of 158 antibody doses were given, including two patients who received two courses of four infusions each. One patient developed acute respiratory failure after the second dose and required assisted ventilation. There was no immediate relationship to the antibody infusion and no evidence of infection. This complication resolved and the patient successfully completed the full course of the antibody treatment. Another patient discontinued therapy after the second dose owing to intolerable fever and painful erythema. Sixty percent of the first, and 20% of subsequent rituximab infusions were associated with infusion-related reactions including mild fever, chills, and occasional skin eruptions. Complete and partial responses were achieved in 24% and 35% of 34 evaluable patients, respectively, for an overall response rate of 59%. The median time to progression/relapse in responding patients was 16 mo (95% CI, 6.4, 25.6) compared with a median of 3 mo duration of response to the immediate previous therapy in these patients. Longer response duration post rituximab monotherapy than with previous treatment in this series of heavily pretreated patients suggests a major role for the antibody in the therapy of patients with indolent lymphoma.