Highlights•Much of Covid-19 hyperinflammation is consistent with mast-cell-driven inflammation.•Prevalence of severe Covid-19 is similar to that of mast cell activation syndrome (MCAS).•Drugs inhibiting mast cells (MCs) and their mediators show promise in Covid-19.•None of the authors currently treated MCAS patients with Covid-19 had severe forms or mortality.•The dysfunctional MCs of MCAS may underlie severe acute and chronic Covid-19 illness.AbstractObjectivesOne-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses.MethodsObservations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS.ResultsThe prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19's hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors' treated MCAS patients with Covid-19 suffered severe infection, let alone mortality.ConclusionsHyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.