Introduction: There are few large-scale studies assessing the true risk of epinephrine use during anaphylaxis in adults. We aimed to assess the demographics, clinical characteristics, and secondary effects of epinephrine treatment and to determine factors associated with major and minor secondary effects associated with epinephrine use among adults with anaphylaxis. Methods: From May 2012 to February 2018, adults presenting to the Hôpital du Sacré-Coeur de Montréal (HSCM) emergency department (ED) with anaphylaxis were recruited prospectively as part of the Cross-Canada Anaphylaxis Registry (C-CARE). Missed cases were identified through a previously validated algorithm. Data were collected on demographics, clinical characteristics, and management of anaphylaxis using a structured chart review. Multivariate logistic regression models were compared to estimate factors associated with side effects of epinephrine administration. Results: Over a 6-year period, 402 adult patients presented to the ED at HSCM with anaphylaxis. The median age was 38 years (Interquartile Range [IQR]: 27, 52) and 40.4% were males. The main trigger for anaphylaxis was food (53.0%). A total of 286 patients (71.1%) received epinephrine treatment, of which 23.9% were treated in the pre-hospital setting, 47.0% received treatment in the ED, and 5.0% received epinephrine in both settings. Among patients treated with epinephrine, major secondary effects were rare (1.4% of patients), including new changes to electrocardiogram, arrhythmia, and neurological symptoms. Minor secondary effects due to epinephrine were reported in 50.0% of patients, mainly inappropriate sinus tachycardia (defined as a rate over 100 beats/minute in 30.1%). Major cardiovascular secondary effects were associated with regular use of beta-blockers (aOR 1.10 [95%CI, 1.02, 1.18]), regular use of ACE-inhibitors (aOR 1.16 [95%CI, 1.07, 1.27]), and receiving more than two doses of epinephrine (aOR 1.09 [95%CI, 1.00, 1.18]). The model was adjusted for age, history of ischemic heart disease, trigger of anaphylaxis, presence of asthma, sex, and reaction severity. Inappropriate sinus tachycardia was more likely in females (aOR 1.18 [95%CI, 1.04, 1.33]) and palpitations, tremors, and psychomotor agitation were more likely in females (aOR 1.09 [95%CI, 1.00, 1.19]) and among those receiving more than two doses of epinephrine (aOR 1.49 [95%CI, 1.14, 1.96]). The models were adjusted for age, regular use of medications, history of ischemic heart disease, triggers of anaphylaxis, presence of asthma, reaction severity, and IV administration of epinephrine. Conclusion: The low rate of occurrence of major secondary effects of epinephrine in the treatment of anaphylaxis in our study demonstrates the overall safety of epinephrine use.