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With the dramatic improvements in outcomes following alternative donor hematopoietic stem cell transplantation (HSCT), interest in the use of alternative donors in severe aplastic anemia (SAA) is increasing. We conducted a multicenter prospective study to explore the efficiency and safety of upfront HSCT from a 6–8/8 HLA-matched unrelated donor (MUD) or 6–7/8 HLA-matched related donor (MRD) in acquired SAA patients under 40 years. Between August 2014 and July 2017, 115 patients were enrolled, including 48 (41.7%) patients receiving grafts from an 8/8 MUD, 25 (21.7%) from a 6–7/8 MRD, and 42 (36.5%) from a 6–7/8 MUD. The incidence of grade II–IV acute graft-versus-host disease (GVHD) was higher in the 6–7/8 MUD group than in the 8/8 MUD group (42.9% vs. 12.8%, P=0.001). The corresponding incidence in the 6–7/8 MRD group was comparable to that in the 8/8 MUD group (21.7% vs. 12.8%, P=0.332). There was no significant difference in the incidence of chronic GVHD (24.3%, 13.6%, and 17.9%, P=0.676), graft failure (2.4%, 8.0%, and 6.3%, P=0.551), overall survival (85.7%, 96.0%, and 87.5%, P=0.424), and failure-free survival (83.3%, 88.0%, and 83.3%, P=0.885) among the three groups (6–7/8 MUD, 6–7/8 MRD, and 8/8 MUD). In multivariate analysis, conditioning regimen without low-dose irradiation or busulfan was associated with an inferior failure-free survival (HR=2.973, P=0.042). In conclusion, after an intensified conditioning regimen with additional low-dose irradiation or busulfan, the outcome of HSCT from a 6–7/8 MRD or 6–7/8 MUD is comparable to that from an 8/8 MUD. [ABSTRACT FROM AUTHOR]