Since the first appearance of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in December 2019, the disease has displayed a remarkable interindividual variability in the global population, resulting in different mortality and morbidity rates. Still, an effective cure against SARS-CoV-2 has not been developed, and therefore, alternative therapeutic protocols must also be evaluated. Considering that stem cells, especially Mesenchymal Stromal Cells (MSCs), are characterized by both regenerative and immunomodulatory properties and that their safety and tolerability have been investigated previously, these cells could potentially be applied against coronavirus disease 19 (COVID-19). In addition, an individual's genetic background is further related to disease pathogenesis, especially rare Inborn Errors of Immunity (IEIs), autoantibodies against Interferon type I, and the presence of different Human Leukocyte Antigens (HLA) alleles, which are actively associated with protection or susceptibility in relation to SARS-CoV-2. Herein, the use of MSCs as a potential stem cell therapy will require a deep understanding of their immunomodulatory properties associated with their HLA alleles. In such a way, HLA-restricted MSC lines can be developed and applied precisely, offering more solutions to clinicians in attenuating the mortality of SARS-CoV-2.