Vaccination is generally recommended for patients with adrenal insufficiency receiving glucocorticoid replacement therapy because they are at risk of experiencing adrenal crisis during infections. Conventional vaccinations, such as those for influenza virus, have rarely been associated with adrenal crisis in patients with adrenal insufficiency; therefore, increasing the glucocorticoid dose during vaccination is not necessarily recommended. The COVID-19 mRNA vaccines exhibit a higher degree of adverse reactions, including fever and general fatigue, than those of conventional vaccines. Here, we present 3 cases of adrenal crisis associated with mRNA COVID-19 (BNT162b2) vaccination in patients with secondary adrenal insufficiency. Two patients presented with adrenal crisis after the second dose, whereas 1 presented with adrenal crisis after the first dose. Within 24 hours of vaccination, all patients presented with fatigue and appetite loss, and 2 patients were febrile. None of them increased their glucocorticoid dosage at the time of vaccination, leading to an adrenal crisis. To date, 9 cases of adrenal crisis, including ours, associated with COVID-19 vaccination have been reported. Considering the high degree of adverse reactions to COVID-19 vaccination, administration of prophylactic stress dose of glucocorticoids is strongly recommended, particularly in patients with symptomatic adverse reactions, to protect them from adrenal crisis.