Background The superiority of Tacrolimus (Tac) as primary immunosuppression for heart transplantation (HT) compared with cyclosporine (CsA) is still under debate. Outcomes of comparison studies are not consistent; the population of these studies has been limited in western countries. The aim of this study was to evaluate outcomes of patients undergoing HT based on primary immunosuppression regime. Methods and Results We analyzed a single-center registry of HT patients between 1999 and 2010, comparing outcomes based on primary immunosuppressions (Tac or CsA). All patients underwent induction therapy with basiliximab and adjunctive maintenance therapy with mycophenolate mofetil and steroids. A total of 176 patients entered the study: 59 received Tac and 117 CsA. There were no differences between groups in baseline characteristics, except for mean follow-ups of 27.1 짹 1.6 months in Tac group and 64.3 짹 3.7 months in the CsA group. Survival within 2 years after HT was different between two groups (98.3% vs. 92.3%, p=0.123 for Tac vs. CsA). The incidence of biopsy proven acute rejection of grade ��� 2R within 6 months after HT, was 5.1% for Tac vs. 23.1% for CsA (p=0.003). Incidence and pattern of infections were comparable between groups, as was renal function. No significant differences emerged between groups for clinically relevant adverse events: post-transplant arterial hypertension; dyslipidemia; hyperkalemia; malignancies. Conclusions In our series the use of tacrolimus resulted in improved survival compared with cyclosporine. And primary use of Tac during antibody induction resulted in superior prevention of acute rejection without an associated increase in infections.