Our knowledge of coronavirus disease-2019 (COVID-19) and its cardiovascular implications is growing every day. The pandemic has raised the question of whether to continue offering heart transplantations due to concerns regarding the risk for exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during hospitalization and challenges in curbing the infection with high levels of immunosuppression. We present the case of a 47-year-old woman who presented with COVID-19 on immunosuppression therapy due to recent heart transplantation four months before admission. The patient’s condition worsened, and despite monitoring and treatment updates, she died on day 19 of admission. Although most immunocompromised persons effectively clear a SARS-CoV-2 infection, this case highlights the potential for ongoing and accelerated viral evolution associated with an immunocompromised state. Patients can manifest acute rejection in the months following transplantation surgery, which can ultimately lead to death.