Patients with steroid-refractory acute graft-versus-host disease (aGVHD) have a high mortality due to infections and progressive aGVHD. We investigated the combined use of 2 monoclonal antibodies (Mabs), daclizumab and infliximab in steroid-refractory aGVHD to selectively control the proliferation of alloreactive T cells and to target 2 different points in the cytokine cascade responsible for this complication. Twenty-two consecutive children who developed 25 episodes of steroid-refractory aGVHD after hematopoietic stem cell transplantation at our institution between September 2002 and July 2007 were treated with combination Mab therapy. Nineteen out of 22 patients responded, with a median response time of 15 days from the start of Mab therapy. Seven patients developed recurrent GVHD, 3 of whom received a second course of Mabs. Seven out of 22 patients developed chronic GVHD. There were 13 episodes of viral reactivations, 4 patients developed probable fungal infections. Impressively, however, there were only 2 infection-related deaths. Interferon-gamma enzyme-linked immunospot assays on selected patients showed preservation of responses to cytomegalovirus and Epstein-Barr virus and the ability to mount de novo responses to these pathogens after Mab therapy. At a median follow-up of 31 months, 15 of the 22 (68%) children are alive. The causes of death were progressive GVHD (3), obliterative bronchiolitis (2), and sepsis (2). These data suggest that combination treatment with daclizumab and infliximab is an effective therapeutic option for patients with steroid-refractory GVHD and seems to be associated with a low infection-related mortality compared with previous therapies.