The rationale for immunosuppressive therapy of thrombotic thrombocytopenic purpura (TTP) was established by observations that TTP may be caused by autoantibodies to ADAMTS13. Patients with high-titer autoantibodies to ADAMTS13 may have a higher mortality, and survivors may require prolonged plasma exchange therapy in spite of adjunctive glucocorticoid treatment. More intensive immunosuppressive therapy with rituximab may provide benefit for many of these patients. The Transfusion Medicine/Hemostasis Clinical Trials Network is developing a randomized, clinical trial to test the hypothesis that addition of rituximab to standard treatment of TTP with plasma exchange and glucocorticoids will decrease initial treatment failure rates as well as subsequent relapses over the following 3 years. To provide the background data for this clinical trial, a systematic review of all published reports on rituximab treatment of immune-mediated disorders was performed. Twelve articles have reported 27 patients treated with rituximab for TTP, with benefit described in 25 (93%) of the patients. Additional reports have described rituximab treatment of 37 other immune-mediated disorders, with clinical response in most patients. These observations from small uncontrolled case series provide the background and rationale for a randomized clinical trial to establish the role of rituximab in the management of patients with TTP.