We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day −1. All patients received T-cell–replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.