BACKGROUND: Allergic reactions to the coronavirus 2019 disease (COVID-19) mRNA vaccine (BNT162b2) were originally reported at higher rates than expected, contributing to vaccine hesitancy and, in some cases, unnecessary vaccine avoidance. Identification of a test that accurately predicts allergic reactions to mRNA vaccines is critical to improve patient care, particularly given the growing use of mRNA-based technologies. OBJECTIVE: We sought to determine the value of basophil activation tests (BATs) in predicting allergic reactions to the BNT162b2 vaccine. METHODS: Blood from 16 participants enrolled in the clinical trial COVID Vaccine Allergy Reaction (COVAAR [ClinicalTrials.gov identifier NCT04977479]) who reported a systemic allergic reaction to their first dose of the COVID-19 mRNA vaccine was drawn before the second or booster dose and incubated with varying concentrations of the BNT162b2 vaccine or the vaccine component dimyristoyl glycerol-polyethylene glycol 2000. Basophil activation was quantified by CD63 expression via flow cytometry. In addition, 8 healthy volunteers (HVs) who tolerated the vaccine were included as controls. RESULTS: Basophil responses to dimyristoyl glycerol-polyethylene glycol 2000 or the BNT162b2 vaccine were not higher among the COVAAR participants than among the HVs. Basophil responses did not correlate with time elapsed since last vaccine administration or previous COVID-19 infection. Instead, in both the HV and COVAAR groups, basophil reactivity was greater among those individuals who had received 2 or more vaccine doses than in those who had received only 1 dose. CONCLUSION: The BAT cannot predict allergic reactions to the BNT162b2 vaccine, and number of previous vaccinations received could be a confounding factor for interpreting the results of the BAT. Further studies are necessary to find a test that can accurately predict allergic reactions to the mRNA vaccine.