Long-term outcomes after heart transplantation are better with immunosuppression with sirolimus than with calcineurin inhibitor. Patients who underwent heart transplantation were treated either with calcineurin inhibitor alone (n = 134) or were switched from calcineurin inhibitor to sirolimus (n = 268) after assessment of their primary immunosuppression. Switching to sirolimus therapy was associated with a significant reduction in plaque volume and plaque index (P < 0.0001 for each). During follow-up (mean 8.9 years), sirolimus therapy was associated with fewer events related to cardiac allograft vasculopathy (adjusted HR 0.35, 95% CI 0.21–0.59, P < 0.0001) and lower all-cause mortality (adjusted HR 0.47, 95% CI 0.31–0.70, P = 0.0002) compared with calcineurin inhibitor therapy. Earlier conversion to sirolimus therapy (≤2 years after transplantation) was associated with better outcomes than later conversion.