BACKGROUND Heart transplant recipients are at increased risk of developing malignant neoplasms. Administration of the calcineurin inhibitors cyclosporine A (CSA) or tacrolimus (TAC) may contribute to this risk. METHODS We compared tumor incidence in heart transplant recipients receiving either CSA (n=25) or TAC (n=120) as maintenance immunosuppressive therapy. Exclusion criteria were therapy with mammalian target of rapamycin-inhibitors, death within the first postoperative year, re-transplantation, and age less than 18 years. RESULTS The 2 study groups were comparable with respect to sex, primary and concomitant diagnoses, and mean follow-up (60.7 ± 19.3 months in the CSA group vs. 59.8 ± 18.1 months in the TAC group; P=0.81). The CSA group was, however, significantly older compared with the TAC group (58.8 ± 11.4 years vs. 49.1 ± 13.0 years, P=0.001), as was the donor age of the CSA group (43.2 ± 11.2 years vs. 37.0 ± 11.7 years, P=0.02). In the CSA group, 5 patients (20%) developed malignant neoplasms compared with 10 patients (8.3%) in the TAC group (P=0.14). Covariate-adjusted 5-year tumor-free survival was comparable between groups (relative risk for the CSA group =1.162 [95% CI: 0.378-3.572; P=0.794]). Moreover, covariate-adjusted 5-year overall survival did not differ between the 2 groups (relative risk for the CSA group =1.95 [95% CI: 0.53-7.19; P=0.36). The incidence of infection, acute rejection, graft vasculopathy, renal failure, and neurological complications was also comparable between the 2 groups. CONCLUSIONS Our data indicate that tumor incidence does not significantly differ in patients receiving CSA or TAC as maintenance therapy.