Background: Imported fire ant (IFA) whole-body extract subcutaneous immunotherapy (IT) is a safe and effective treatment for IFA hypersensitivity, with a recommended length of treatment of 3 to 5 years. Objective: To evaluate long-term IFA IT adherence in patients with IFA allergy living in an endemic area. Methods: During 2007 to 2014, patients with IFA-sting systemic reactions and a recommendation to start IFA IT were prospectively enrolled in this study. Subjects were contacted annually for interval IT adherence. Institutional review board approval was obtained. Results: A total of 87 subjects, ages 2 to 64 years, with a recommendation to initiate IFA IT, were enrolled. Subjects were predominantly adult (76%) and female (55%), and 30% had asthma. Of these patients, 77 (89%) initiated treatment within 1 year of recommendation; 18 (23%) adhered to a 3-year course; and 10 (13%) adhered to a 5-year course. At 3 years, there were no significant differences in adherence between male and female subjects (28% vs 19%, P =.33), children and adults (25% vs 22%, P =.79), or those with or without asthma (30% vs 20%, P =.31). Adherence in subjects with mild initial reactions was lower than in subjects with moderate-to-severe reactions (0% vs 25%, P =.05) at 3 years only. Conventional buildup and concurrent flying Hymenoptera venom immunotherapy were predictive of adherence. Reasons for discontinuation were relocation to a nonendemic area (29%) and inconvenience (27%). Conclusion: This study showed poor long-term adherence to IFA IT at 3 and 5 years. Initial sting severity, buildup protocol, and concurrent flying Hymenoptera venom immunotherapy were predictors for long-term IT adherence.