De novo donor-specific antibodies (DSAs) are associated with increased risk of antibody-mediated rejection and worse clinical outcomes after orthotopic heart transplant (OHT). No study has reported the production of DSAs after infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in an OHT population. In this retrospective study, we described coronavirus disease 2019 (COVID-19) incidence and clinical course in a large, contemporary OHT cohort. We showed that the case-fatality rate has significantly decreased since the early days of the pandemic, although remains higher than that of the general population. In addition, we found that 10% of OHT recipients developed de novo DSAs or experienced an increase in pre-existing DSAs after COVID-19, with the majority occurring in unvaccinated patients (15% vs 2%). Further studies are necessary to substantiate our findings in an external cohort.