The precise amount of epinephrine needed to reverse severe symptomatology due to an anaphylactic reaction is unknown. We tried to determine how frequently more than one injection of epinephrine is required to treat an anaphylactic reaction. A retrospective review of patient charts with anaphylactic reactions requiring epinephrine, in response to inhalant allergen and hymenoptera venom immunotherapy as well as live hymenoptera stings, examined type of reaction; number, doses, and timing of epinephrine administered; and ancillary treatment. A total of 105 anaphylactic reaction events of varying severity (Ring's classification) were recorded (54 - Grade I, 29 - Grade II, 18 - Grade III, 0 - Grade IV, 4 - unknown). The median epinephrine dose administered was 0.3 cc (range 0.1 to 0.8 cc, 1:1000). The timing of the first epinephrine injection was ≤5 minutes in 27, 6–10 minutes in 13, 11–30 minutes in 16, ≤30 minutes in 32, 31–60 minutes in 12, and >60 minutes in five epinephrine treated patients. Overall, 38 patients (35.5%; CI95, 26.4–44.6%) required >1 epinephrine injection. Of these, 11 experienced Grade I (11/54–20.3%; CI95, 9.6–31.0%), 12 - Grade II (12/29–41.5%, CI95, 23.5–59.3%), and 13 - Grade III (13/18–72.2%, CI95, 51.5–92.9%); reactivity was unknown in 2 patients. Forty-four patients also received an antihistamine, 10 received corticosteroids, and 30 received both medications and/or other ancillary therapy. A significant number of patients (>35%) with anaphylactic reactions received greater than one epinephrine dose to manage events for the three classes of severity. Patients at risk for anaphylaxis and their caregivers need to recognize that more than one dose of epinephrine may be required for treatment of anaphylaxis.