The mRNA vaccines developed by Pfizer–BioNtech and Moderna use a lipid-based nanoparticle carrier system that prevents the rapid enzymatic degradation of mRNA and facilitates in vivo delivery.1,2,7 This lipid-based nanoparticle carrier system is further stabilized by a polyethylene glycol (PEG) 2000 lipid conjugate that provides a hydrophilic layer, prolonging half-life. Although the technology behind mRNA vaccines is not new, there are no licensed mRNA vaccines, and the Pfizer–BioNtech and Moderna vaccines are the first to receive an EUA. There is therefore no prior experience that informs the likelihood or explains the mechanism of allergic reactions associated with mRNA vaccines. It is possible that some populations are at higher risk for non–IgE-mediated mast-cell activation or complement activation related to either the lipid or the PEG-lipid component of the vaccine. By comparison, formulations such as pegylated liposomal doxorubicin are associated with infusion reactions in up to 40% of recipients; the reactions are presumed to be caused by complement activation that occurs on first infusion, without previous exposure to the drug, and they are attenuated with second and subsequent injections.8