Immune thrombocytopenic purpura (ITP) is mediated by antiplatelet autoantibodies possibly involving CD40:CD40L co-stimulation. Two humanized anti-CD40L monoclonal antibodies, hu5c8 and IDEC-131, were evaluated in 46 patients with chronic refractory ITP. Fifteen patients were treated with 20 mg/kg of hu5c8: four (27%) had complete responses (CR) and two (13%) had partial responses (PR). Three responders to hu5c8 were successfully retreated with IDEC-131, demonstrating its efficacy. Thirty-one subsequent patients were treated with 5–20 mg/kg per infusion of IDEC-131: five (16%) responded (one CR and four PR). The 24% (11/46) overall response rate demonstrates the potential role of CD40-CD40L in the pathogenesis of ITP.