Background: Large local reactions are not uncommon during allergen immunotherapy (AIT). Dosage adjustments after large local reactions are commonly instituted despite literature that suggests individual large local reactions do not seem to predict subsequent systemic reactions. Objective: To investigate the relationship between large local reactions and the risk of systemic reactions to AIT. Methods: Retrospective review of the AIT database of a large, multicenter allergy practice group was conducted between June 1, 2003, and May 31, 2005. Numbers of large local reactions in 258 patients who experienced systemic reactions to AIT were compared with 299 age-, sex-, and sensitivity-matched control patients who did not experience systemic reactions during AIT. Results: A total of 283 systemic reactions occurred in 258 patients during the surveillance period, which included 661,123 patient visits for 1,108,621 allergy injections. The systemic reaction rate was 0.043% of visits and 0.025% of injections. The large local reaction rate was 35.2% of visits and 19.5% of injections among systemic reactors compared with 8.9% of visits and 5.3% of injections in the controls (P < .001 each). Thus, the odds of experiencing large local reactions were significantly increased among systemic reactors. Conclusions: Although AIT is a safe and effective immunomodulatory therapeutic option for the treatment of allergic diseases, patients with increased frequency of large local reactions may have increased risk for future systemic reactions. Identifying additional risk factors remains viable. Recognizing the relevance of frequent large local reactions is important for designing safer protocols for successful AIT in these patients.