Anti‐thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation to prevent severe graft‐versus‐host disease (GVHD) and graft failure. However, overexposure to ATG may increase cytomegalovirus (CMV), Epstein‐Barr virus (EBV) reactivation, non‐relapse mortality, and disease recurrence. To investigate the optimal dosing of ATG, we established a targeted dosing strategy based on ATG concentration monitoring for haploidentical peripheral blood stem cell transplantation (haplo‐PBSCT). The aim of this phase 2 trial is to evaluate the safety and efficacy of the ATG‐targeted dosing strategy in adult unmanipulated haplo‐PBSCT. ATG was administered for 4 days (−5 days to −2 days) during conditioning. The ATG doses on −3 days and −2 days were adjusted by our dosing strategy to achieve the optimal ATG exposure. The primary endpoint was CMV reactivation on +180 days. Between December 2020 and January 2022, 66 haplo‐PBSCT patients were enrolled and 63 of them were evaluable with a median follow‐up of 632 days. The cumulative incidence of CMV reactivation was 36.7% and that of EBV was 58.7%. The 1‐year disease‐free survival was 82.5%, overall survival was 92.1%, and CD4+ T‐cell reconstruction on +100 days was 76.8%. The most common severe regimen‐associated toxicities (> grade 3) were infections (51.5%) and gastrointestinal toxicity (25.5%). A total of 102 haplo‐PBSCT patients who received the conventional fixed ATG dose (cumulative 10 mg/kg) comprised historical control. The outcomes in historical control were inferior to those of phase 2 trial cohort (CMV reactivation: 70.8%, p < .001; EBV reactivation: 76.0%, p = .024; CD4 + T‐cell reconstruction: 54.1%, p = .040). In conclusion, ATG‐targeted dosing strategy reduced CMV/EBV reactivation and improved survival without increasing GVHD after haplo‐PBSCT. These advantages may be associated with accelerated immune reconstitution.