Background: Although local reactions (LR) to subcutaneous immunotherapy (SCIT) occur in 26-86% of patients, there are no well-studied strategies to manage LRs. Objective: To complete a prospective, randomized, single-blind, controlled trial that compared pre-rinsing SCIT syringes with diphenhydramine, epinephrine, or placebo in patients who were receiving aeroallergen SCIT and experiencing LRs despite pretreatment with an antihistamine. Methods: Patients ages ≥5 years who were receiving aeroallergen SCIT per a conventional dosing schedule and who were experiencing LRs despite premedicating with an oral antihistamine were randomized to diphenhydramine, epinephrine, or placebo rinse, and were followed up for three subsequent visits. At each visit, the patients were asked (yes or no) if LRs improved. Results: A total of 490 patients were enrolled in the study. Seventy-four of the 490 patients (15.1%) experienced an LR despite pretreatment with an oral antihistamine and were randomized into an intervention group. At visit 1, an epinephrine rinse was strongly associated with decreasing LR compared with both diphenhydramine rinse and placebo (p < 0.001). There was no difference among the intervention groups at visits 2 and 3. In patients who reported a consistent outcome at all three visits, the epinephrine rinse was significantly associated with a decrease in LR compared with both diphenhydramine rinse and placebo rinse (p = 0.05). Conclusion: In patients who received aeroallergen SCIT per a conventional dosing schedule, an epinephrine rinse significantly decreased LR at the first visit, and also within a population that reported a consistent outcome at all three study visits. In patients already premedicating with an oral antihistamine, adding an epinephrine rinse is a safe and effective strategy to decrease LRs to aeroallergen SCIT.