Background: Hypersensitivity to the sting of the imported fire ant (IFA) is a growing and significant cause of morbidity and mortality in the United States. Conventional immunotherapy with IFA whole body extract (WBE) has been shown to be effective; however, rush immunotherapy (RIT) with IFA WBE has not been studied. Objective: In this study, we evaluated the safety and efficacy of RIT with IFA WBE and sought to determine whether prophylactic pretreatment with antihistamines and steroids reduces the systemic reaction rate associated with RIT. Methods: Patients with IFA hypersensitivity were randomized to placebo or twice-daily terfenadine 60 mg, ranitidine 150 mg, and prednisone 30 mg initiated 2 days before RIT in a double-blinded study. The 2-day RIT protocol consisted of hourly injections to achieve a final dose of 0.3 mL 1:100 wt/vol. Patients returned on day 8 to receive 2 hourly injections of 0.25 mL 1:100 wt/vol (total, 0.5 mL) and again on day 15 for a single injection of 0.5 mL 1:100 wt/vol. Efficacy of the protocol was determined on day 22, a pair of IFA sting challenges being performed 2 hours apart. Results: Fifty-nine patients were enrolled into the study; a total of 58 patients (age range, 18 to 49 years) initiated the 2-day RIT. Only 3 patients (5.2%) experienced a mild systemic reaction during the protocol. Among those experiencing a systemic reaction with RIT, there was no statistical difference between the 2 premedication groups (3.6% active and 6.7% placebo; P = .87). Sting challenges were performed on 56 patients for a total of 112+ stings; only 1 mild systemic reaction occurred (efficacy, 98.2%). Conclusion: RIT with IFA WBE for IFA hypersensitivity is both safe and efficacious; the rate of mild systemic reactions is low. Premedication is not necessary, inasmuch as prophylactic pretreatment with antihistamines and steroids did not reduce the systemic reaction rate associated with RIT. (J Allergy Clin Immunol 2002;109:556-62.)