BACKGROUND Antithymocyte globulin (ATG) is an important component of conditioning regimens to prevent severe graft‐versus‐host disease (GVHD) in patients undergoing unmanipulated, haploidentical stem cell transplantation (haplo‐SCT). However, to the authors' knowledge, the optimal dose of ATG is unknown. METHODS In this prospective, randomized trial, the authors compared the long‐term outcomes of 2 ATG doses (rabbit thymoglobulin) used in myeloablative conditioning before unmanipulated haplo‐HSCT. Patients were randomly assigned (1:1) to received 10 mg/kg (ATG‐10) or 6 mg/kg (ATG‐6) of ATG. Analysis of disease‐free survival, GVHD‐free/recurrence‐free survival (GRFS), disease recurrence, nonrecurrence mortality, and chronic GVHD (cGVHD) included the entire population. Late effects were assessed in disease‐free patients who had survived for at least 6 months and had received regular follow‐up evaluations. RESULTS A total of 224 patients were recruited. The median follow‐up period was 1614 days (range, 28‐1929 days). The rate of infection‐related deaths in ATG‐10 arm was double that of the ATG‐6 arm (14.3% vs 7.1%; P = .084). The 5‐year cumulative incidence was comparable between the ATG‐6 and ATG‐10 groups for disease recurrence (12.8% vs 13.4%; P = .832) and nonrecurrence mortality (11.6% vs 17.0%; P = .263). The 5‐year probability of disease‐free survival was comparable between the groups (75.6% vs 69.6%; P = .283). The 5‐year cumulative incidence of cGVHD was found to be higher with ATG‐6 (75.0% vs 56.3% P = .007 and moderate‐to‐severe cGVHD: 56.3% vs 30.4% P<.0001) as well as that for late effects (71.2% vs 56.9%; P = .043). The 5‐year probability of GRFS was higher in the ATG‐10 group (41.0% vs 26.8%; P = .008). In the multivariate analysis, ATG‐10 was found to be associated with a lower risk of cGVHD and improved GRFS. CONCLUSIONS ATG‐10 was found to be associated with better GVHD prevention and superior GRFS, but an increase in infection‐related deaths. Cancer 2017;123:2881–92. © 2017 American Cancer Society. Considerable progress has been made in unmanipulated haploidentical hematopoietic stem cell transplantation with an antithymocyte globulin (ATG)‐based conditioning regimen. The findings of the current study suggest that ATG at a dose of 10 mg/kg is associated with better prevention of graft‐versus‐host disease and superior graft‐versus‐host disease‐free/recurrence‐free survival, but an increased rate of infection‐related deaths. The optimal dose of ATG in the setting of unmanipulated haploidentical hematopoietic stem cell transplantation should be investigated further.