BACKGROUND: In cardiac transplantation, high-dose antithymocyte globulin (ATG) induction therapy as short-term rejection prophylaxis has not been used. OBJECTIVE: To evaluate the efficacy and safety of intraoperative use of single high-dose ATG induction therapy after heart transplantation. PATIENTS AND METHODS: Fourteen patients received single high-dose ATG therapy plus shortened standard therapy (group1), and 16 patients received ATG standard therapy (group2). RESULTS: No perioperative deaths were reported. During follow-up, 3 deaths were recorded. Five-year patient survival was 92.8% in groupl vs 85.7% in group2 (P = .34). The mean (SD) number of acute rejection episodes per patient was 2.5 (2.2) in the high-dose ATG group vs 2.7 (2.5) in the standard therapy group (P = .83), with 5-year freedom from acute rejection of 45.5% in group 1 vs 35.6% in group 2 (P = .85). Infections were observed in 6 patients in group1 and in 8 patients in group2 (P = .69). Malignant disease was diagnosed in 1 patient in the high-dose group and 3 patients in the standard therapy group (P = .35). Chronic allograft vasculopathy was recognized in 4 patients (28%) in group1 and 8 (50%) in group2 (P = .05). Five-year actuarial freedom from allograft vasculopathy was 69.2% in the high-dose ATG group vs 50.0%% in the standard therapy group (P = .35). CONCLUSIONS: High-dose ATG for prevention of rejection episodes is safe and efficacious, with a lower rate of early and late complications, in particular, graft vasculopathy.