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Cardiac-allograft vasculopathy (CAV) is the main cause of morbidity and mortality among patients who have undergone heart transplantation. Long-term immunosuppression with calcineurin inhibitors (CNIs) contributes to CAV progression; sirolimus might provide an alternative for primary immunosuppression.To determine whether replacement of CNIs with sirolimus as primary immunosuppression prevents CAV progression in heart transplant recipients.This observational, open-label, single-center study involved a cohort of heart transplant recipients recruited between January 2004 and July 2006. Patients who had impaired renal function secondary to CNI and/or CAV and had undergone two consecutive three-dimensional intravascular ultrasound (IVUS) examinations were eligible for conversion to sirolimus immunosuppression (sirolimus group) with unchanged secondary immunosuppression. A group of cardiac transplant recipients who were maintained on standard primary immuno-suppression with ciclosporin or tacrolimus and had undergone two IVUS examinations within the same time frame served as controls (CNI group); the groups were not matched. IVUS examinations for the study were performed before conversion to sirolimus or entry to the CNI group and at 1 year.The primary outcome measures were plaque volume (PV), vessel volume, and plaque index (PI) calculated as (PV/vessel volume) × 100%.The study enrolled 69 demographically similar patients, 29 of whom were allocated to the sirolimus group and 40 to the CNI group. Conversion to sirolimus occurred at a mean of 3.81 ± 3.4 years after cardiac transplantation. On enrollment, the sirolimus group had a higher incidence of previous rejections and worse renal function. At follow-up, the lipid profile of the sirolimus group was worse than that of the CNI group. Mean progression in PV and PI was slower in the sirolimus group than in the CNI group (0.1 ± 1.13 vs 1.28 plusmn 2.86 mm3/mm; P = 0.0041 and 0.1 ± 8% vs 6 plusmn; 8%; P = 0.005, respectively). Disease progression was detected in 48% of the sirolimus group compared with 82% of the CNI group (P = 0.0025). After adjustment for age at first IVUS, donor age, indication for transplantation, presence of hypertension and diabetes, ischemic time and baseline value of PV, the differences in PV and PI between the two groups remained significant (P = 0.001 and P = 0.009, respectively). Conversion to sirolimus within 2 years of transplantation slowed progression of PV and PI compared with continued CNI (0.06 ± 1.06 vs 1.77 ± 1.65 mm3/mm; P = 0.009 and 0 ± 9% vs 10% ± 8%; P = 0.029, respectively), but conversion to sirolimus more than 2 years after transplantation did not slow progression of PV or PI. No changes were observed in vessel volume in either treatment group. Progression of PV or PI was not affected by choice of second immunosuppressant in either treatment group.Primary immunosuppression with sirolimus seems to attenuate CAV, probably because of the antiproliferative effects of this agent.