Background: Home reactions requiring epinephrine administration, a marker of their severity, restrict the widespread use of oral immunotherapy (OIT), but their risk factors are largely not known. Objective: To identify risk factors for such reactions during OIT to most allergenic foods. Methods: All patients who began OIT for peanut, tree nuts, sesame, or egg allergy at the Shamir Medical Center between April 2010 and January 2020 were enrolled. The patients were instructed to use their epinephrine autoinjectors during reactions consisting of severe abdominal pain, significant shortness of breath, or lethargy, or whenever in uncertainty of reaction severity. Patients with and without home epinephrine-treated reactions (HETRs) were compared. Results: A total of 757 OIT treatments for peanut (n = 346), tree nuts (n = 221; walnut n = 147, cashew n = 57, hazelnut n = 16, almond n = 1), sesame (n = 115), and egg (n = 75) allergies were administered to 644 patients. Eighty-three (10.9%) patients experienced HETRs. The highest rate of HETRs was experienced during walnut (20.4%) or hazelnut (25%) OIT, followed by peanut (9.8%), sesame (6.1%), egg (6.7%), and cashew (5.3%) OIT. Risk factors for HETRs included a reaction treated in an emergency department (ER) (P = .005) before starting OIT and a reaction treated with epinephrine during in-clinic induction (P < .001). Significantly fewer patients with (73.6%) than without (88.3%) HETRs achieved full desensitization (P = .001), but only a few patients with HETRs (8.4%) failed treatment. Conclusion: Previous reaction severity is the main predictor for HETRs during OIT. These reactions are more frequent during walnut and hazelnut OIT than during OIT for other foods studied. Most patients experiencing HETRs achieved desensitization.