BackgroundGiven the choice of standard, cluster, and rush build-up for aeroallergen immunotherapy, standard-build immunotherapy has generally been preferred because of a perceived high rate of systemic reactions (SRs) associated with cluster and rush immunotherapy. ObjectiveTo characterize the incidence of SRs during standard, cluster, and rush build-up immunotherapy in an allergy practice during a 5-year period. MethodsA retrospective review was conducted among patients receiving standard-build, 8- to 10-step cluster, or 2-day rush immunotherapy from January 1, 2010, through December 31, 2014, at Family Allergy & Asthma clinics in Louisville, Kentucky. Investigators excluded reactions that occurred during skin prick testing, venom immunotherapy, and not-true SRs, and identified the build-up method, age, sex, date of reaction, vial concentration, and presence of asthma. Per-shot and per-patient incidence of SRs was computed from these data. ResultsDuring our review period, 2,549,643 injections were administered to 11,982 patients. Per-shot incidence of SR was 0.01%, 0.06%, and 0.33% for standard, cluster, and rush immunotherapy, respectively; per-patient incidence of SR was 2.84%, 2.52%, and 11.86% for standard, cluster, and rush immunotherapy, respectively. A total of 42% of SRs were grade 1, 43% were grade 2, 12% were grade 3, and 3% were grade 4. No fatalities were reported. A total of 70% of total SRs, 75% of cluster SR, and 55% of rush SR occurred in females, with an emergent peak in SR from May to October. ConclusionCompared with previously published rates, we observed a decrease in the incidence of SR for standard, cluster, and rush immunotherapy, with peak seasonality from May to October and a female predominance.