Although several innovative and repurposed drugs have been approved for the treatment of COVID-19 during the last year, we still do not have evidence-based knowledge on the best therapeutic strategy to treat immunocompromised patients. Most treatment guidelines are structured to whether the disease state is mild, moderate, or severe, and not sufficiently according to host factors including host immunity. Whereas the Omicron variant causes less severe diseases in the general population, this is not necessarily the case for individuals with an impaired immune system, such as organ transplant recipients, patients with hematological malignancies, active cancer or primary immunodeficiency, or individuals treated with immunosuppressive drugs for a variety of medical conditions.