Treatment of steroid-resistant acute graft-versus-host disease (GVHD) remains an unmet clinical need. Inolimomab, a monoclonal antibody to CD25, has shown encouraging results in phase 2 trials. This phase 3 randomized, open-label, multicenter trial compared inolimomab vs usual care in adult patients with steroid-refractory acute GVHD. Patients were randomly selected to receive treatment with inolimomab or usual care (the control group was treated with antithymocyte globulin [ATG]). The primary objective was to evaluate overall survival at 1 year without changing baseline allocated therapy. A total of 100 patients were randomly placed: 49 patients in the inolimomab arm and 51 patients in the ATG arm. The primary criteria were reached by 14 patients (28.5%) in the inolimomab and 11 patients (21.5%) in the ATG arms, with a hazard ratio of 0.874 (P = .28). With a minimum follow-up of 1 year, 26 (53%) and 31 (60%) patients died in the inolimomab and ATG arms, respectively. Adverse events were similar in the 2 arms, with fewer viral infections in the inolimomab arm compared with the ATG arm. The primary end point of this randomized phase 3 trial was not achieved. The lack of a statistically significant effect confirms the need for development of more effective treatments for acute GVHD. This trial is registered to https://www.clinicaltrialsregister.eu/ctr-search/search as EUDRACT 2007-005009-24.