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The number of homozygous human leukocyte antigen (HLA) loci has been associated with the risk of HLA sensitization in kidney transplant candidates, which is a risk factor for antibody-mediated rejection (AMR). We assessed the relationship between HLA homozygosity and sensitization and AMR in heart transplant (HT) recipients. The study cohort comprised 1238 HT recipients transplanted 2012 - 2019 (622 Paris, 616 Los Angeles). Calculated panel reactive antibody values were determined with a threshold of mean fluorescence intensity >= 2500 (Los Angeles) or 3000 (Paris) using an 11-locus CPRA calculator based on National Marrow Donor Program HLA genotype frequencies. Split antigens were mapped to the corresponding broad antigen. HLA genotypes were used to assess homozygosity for HLA-A, -B, -DR, and -DQ. "Low" or "high" HLA homozygosity was defined as 0/1/2 or 3/4 homozygous loci. Cox modeling was performed with biopsy-proven AMR by 3 years post-HT as the endpoint. 525 (42%) recipients had CPRA >=1% and 173 (14%) had CPRA >=50%. Homozygosity at HLA-A, -B, -DR, and -DQ occurred in 20%, 8%, 14%, and 29% of candidates, respectively. The number of homozygous HLA loci was associated with increasing CPRA in a linear model (β=2.39/homozygous locus, p=0.008) and in a stepwise fashion (FIG 1). Only the group with CPRA 50-100% and low homozygosity experienced an increased risk of AMR (HR 4.1, 95% CI 2.8-6.2, p<0.001, FIG 2). Homozygosity at multiple HLA loci is associated with an increased risk of sensitization but decreases the risk of AMR in sensitized candidates. Although the mechanism is unknown, we speculate that HLA homozygosity may limit the repertoire of alloreactive T cells. [ABSTRACT FROM AUTHOR]