The development of acute humoral rejection (AMR) in transplanted organs remains a highly relevant and unresolved issue. This study presents a clinical case of heart transplantation (HT) in a patient with hypertrophic cardiomyopathy transitioning to a restrictive phenotype amid chronic lymphocytic myocarditis. Following HT, the patient developed nosocomial pneumonia, necessitating a reduction in immunosuppressive therapy. On the 12th day post-transplantation, the patient experienced a sudden hemodynamic collapse, which proved fatal. Autopsy examination revealed acute humoral rejection with a predominance of CD16+ cells in the infiltrate, exhibiting high expression of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein on the endothelium and CD16+ cells. Further investigation is required to clarify the role of SARS-CoV-2 in potentially exacerbating AMR development.