A recent clinical trial published in theJournal of American Medical Associationrevealed that everolimus combined with low-dose tacrolimus did not show superior efficacy in preventing rejection, cardiac allograft vasculopathy, or chronic kidney disease, but it was safe regarding overall transplant complications at 30 months and may serve as a suitable alternative to tacrolimus with mycophenolate in pediatric recipients. Everolimus has long been considered for transplant care because of its potential to reduce rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV). And yet, its use remains controversial, as early post-transplant introduction has been linked to higher infection-related deaths. This trial enrolled 211 children at 25 U.S. sites between February 2018 and August 2020, with final follow-up in April 2023. The participants, with a mean age of 8.2 years, were randomized at 6-months post-transplant to receive either everolimus plus low-dose tacrolimus (107 children) or the standard regimen of tacrolimus with mycophenolate mofetil (104 children). This research tracked efficacy (MATE-3 score) and safety (MATE-6 score) over 30 months At 30 months, both treatment groups showed comparable rates of rejection, CAV, and CKD. The mean MATE-3 score difference between the groups (−0.32) was not statistically significant. Also, everolimus did not increase safety risks, where the adjusted MATE-6 score was similar between groups and met the non-inferiority threshold of the trial. Graft survival and freedom from major adverse transplant events were also comparable across both regimens, which reassured clinicians that everolimus does not compromise long-term outcomes when initiated 6-months post-transplant. However, the study highlighted 2 notable advantages for the everolimus group. At 12 months, children receiving everolimus and low-dose tacrolimus demonstrated improved kidney function, measured by a higher estimated glomerular filtration rate (average gain of 10.5 mL/min/1.73 m²). Also, everolimus was linked to a 50% lower risk of CMV infection. While everolimus did not outperform standard therapy in preventing rejection, CAV, or CKD at 30 months, these results support its safety when introduced later in pediatric patients. The added benefits of better kidney function and reduced CMV infections may influence how clinicians tailor post-transplant immunosuppression. Almond, C. S., Daly, K. P., Albers, E. L., Alejos, J. C., Ameduri, R., Auerbach, S. R., Barkoff, L., Barnes, A. P., Bock, M. J., Butto, A., Carlo, W. F., Castleberry, C. D., Chrisant, M. R., Deshpande, S. R., Dreyer, W. J., Everitt, M. D., Feingold, B., Gonzales, S., Hollander, S. A., … Ellsworth, D. (2025). Everolimus and Low-Dose Tacrolimus After Heart Transplant in Children. JAMA.https://doi.org/10.1001/jama.2025.14338