BACKGROUND High‐dose, post‐transplantation cyclophosphamide (PTCy) to prevent graft‐versus‐host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1‐antigen human leukocyte antigen (HLA)‐mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients. METHODS A parallel, 2‐arm, nonrandomized phase 2 clinical trial was conducted of melphalan‐based reduced‐intensity conditioning with PTCy, tacrolimus, and mycophenolate mofetil to prevent GVHD in patients with high‐risk hematologic malignancies who underwent HAPLO (n = 60) or 9/10 MUD (n = 46) SCT. RESULTS The 1‐year overall and progression‐free survival rates were 70% and 60%, respectively, in the HAPLO arm and 60% and 47%, respectively, in the 9/10 MUD arm. The day +100 cumulative incidence of grade II to IV acute GVHD and grade III to IV acute GVHD was 28% and 3%, respectively, in the HAPLO arm and 33% and 13%, respectively, in the 9/10 MUD arm. The 2‐year cumulative incidence of chronic GVHD was 24% in the HAPLO arm and 19% in the 9/10 MUD arm. The 1‐year cumulative incidence of nonrelapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, and the 1‐year relapse rate was 19% in the HAPLO arm and 25% in the 9/10 MUD arm. CONCLUSIONS Although this was a nonrandomized study and could not serve as a direct comparison between the 2 groups, the authors conclude that PTCy‐based GVHD prophylaxis is effective for both HAPLO and 9/10 MUD SCTs. Prospective randomized trials will be required to compare the efficacies of alternative donor options for patients lacking HLA‐matched donors. Cancer 2016;122:3316–3326. © 2016 American Cancer Society. After transplantation, combined cyclophosphamide, tacrolimus, and mycophenolate is an effective graft‐versus‐host disease prophylaxis strategy for patients with advanced hematologic malignancies who undergo not only haploidentical donor but also human leukocyte antigen‐mismatched unrelated donor (9/10 MUD) transplantation. The results from this study support melphalan‐based conditioning as an effective regimen for a broad range of hematologic malignancies.