BACKGROUND: Cardiac allograft vasculopathy is an important cause of mortality after heart transplantation (HT). Dyslipidemia is a major contributor to the development of cardiac allograft vasculopathy. The safety and effectiveness of proprotein convertase subtilisin/kexin 9 inhibition to lower cholesterol and to prevent cardiac allograft vasculopathy early after HT are not well established. METHODS: In this investigator-initiated, prospective, multicenter, double-blind randomized trial, participants were randomized early after HT to receive either alirocumab or placebo in addition to rosuvastatin. Before randomization and at 1 year, all participants underwent invasive coronary assessment, including angiography, fractional flow reserve, coronary flow reserve, the index of microcirculatory resistance, and intravascular ultrasound with near-infrared spectroscopy. Lipid values were assessed at baseline and at prespecified intervals. The primary end point was the change in coronary artery plaque volume from baseline to 1 year after HT based on serial intravascular ultrasound. RESULTS: A total of 114 HT recipients were included (57 assigned to alirocumab and 57 assigned to placebo). Baseline characteristics were well matched between the 2 groups. The low-density lipoprotein cholesterol levels decreased significantly from baseline to 1 year in the alirocumab arm (72.7±31.7 to 31.5±20.7 mg/dL; P <0.001) and did not change with placebo (69.0±22.4 to 69.2±28.1 mg/dL; P =0.92). Plaque volume increased numerically in both groups from baseline to 12 months (alirocumab, 176.3±95.2 to 184.5±105.4 mm³; P =0.23; placebo 173.7±96.7 to 183.1±109.8 mm 3 ; P =0.15). The change in plaque volume (mean difference in differences) did not differ between groups (1.01 [0.89–1.14]; P =0.86). Fractional flow reserve, coronary flow reserve, and the index of microcirculatory resistance did not change significantly with the addition of alirocumab. There were no significant adverse events related to alirocumab. CONCLUSIONS: Proprotein convertase subtilisin/kexin 9 inhibition with alirocumab in addition to statin therapy early after HT safely lowers low-density lipoprotein cholesterol but did not reduce coronary artery plaque progression after 1 year compared with rosuvastatin alone in patients with a low baseline low-density lipoprotein cholesterol. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03537742.