Hereditary alpha-tryptasemia (HaT) is an autosomal dominant genetic trait presenting as extra copies of the α-tryptase encoding TPSAB1 gene, resulting in increased quantities of baseline serum tryptase (BST). Tryptase is a pro-inflammatory mediator expressed by mast cells and basophils. Pro-tryptases (inactive) are constitutively secreted into serum and provide the vast majority of measured BST in healthy individuals. By contrast, during IgE-mediated immediate hypersensitivity reactions, mature tryptases (and other mast cell mediators) are released via regulated secretion and contribute to symptoms of Type I allergic reactions such as anaphylaxis. Some affected individuals report few or no symptoms, while others present with a range of debilitating symptoms which can include cardiac, connective tissue, dermatologic, gastrointestinal, and neurologic. BST levels and symptoms display a gene dose relationship with TPSAB1: increasing numbers of α-encoding TPSAB1 copies correlate with higher tryptase levels and greater IgE-mediated symptom severity. It remains to be determined if HaT can also enhance other mast cell-mediated disorders. Vaccine-associated anaphylaxis is exceedingly rare (1.3 cases per million doses). We describe two case studies involving anaphylaxis after vaccination in patients with HaT, and associated Vaccine Adverse Event Reporting System (VAERS) data.