The clinical outcomes of COVID-19 patients highlight a significant minority of subjects with very rapid lethal outcomes subsequent to the almost complete healing after coronavirus infections for most of the subjects involved. In addition, the reckless use of some drugs and therapeutic protocols that have not shown any efficacy in reducing mortality in those patients where the progression of the disease was unstoppable suggests a different interpretative model in the pathogenesis of severe cases. Starting from the clinical data already known for almost twenty years on the behavior of human SARS coronaviruses, it is possible to develop a new hypothesis. The reference points taken into consideration are: i) the comparison of the histological evidence of the autoptic material; ii) the poor pharmacological response in subjects with severe phenotypes of the pathology; iii) the common element of endotheliitis in a subgroup of the population characterized by harmful clinical outcomes during the evolution of the pathology. The tendency to develop widespread, massive endothelial lesions not responding to any drug therapy or other interventions necessarily plays a crucial role in the onset of the systemic and severe stage of the disease. The present perspective opens the door to a different therapeutic approach both to the full-blown phase of COVID-19 and to the preventive phase or the very first manifestations of the disease. It is imperative to pay more attention to the protection of the vascular endothelium in subjects who already have a predisposition to the development of a severe evolution of this ailment rather than to give a simple antiviral therapy together with symptomatic drugs.