Acute tumor lysis syndrome (ATLS) is a recognized complication of the treatment of malignant lymphomas and is associated with significant morbidity and mortality. However, there have been few reports of the occurrence of ATLS in patients treated with rituximab. This study reports 2 patients with high-grade diffuse large B-cell non-Hodgkin's lymphoma who presented high tumor load, were sensitive to treatment and had multiple risk factors for ATLS. Both patients developed ATLS after treatment with rituximab and, despite aggressive supportive therapy, died of multiple organ failure. These cases illustrate that ATLS can occur after treatment with rituximab and that a high index of suspicion is necessary for the prompt diagnosis of ATLS.