OBJECTIVE To determine the magnitude of immunoglobulin E (IgE) variability in a cohort of patients with severe asthma considered for omalizumab therapy. METHODS Retrospective chart review identified 65 patients with two or more IgE determinations out of the 124 patients referred to the Cleveland Clinic Respiratory Institute for treatment with omalizumab from 2003 to 2011. Patients with conditions known to affect IgE concentrations were excluded. Demographic data, pulmonary function testing, medications, smoking status, and atopy were recorded. The range of variability and percent variability in relation to baseline serum IgE were calculated. RESULTS The median difference of serum IgE between the minimal and maximal values was 94.9 IU/ml (IQR 26.3-324.1 IU/ml). Percent variability from minimum value had a median of 75.5% (IQR 23.3-152.6%). There was no correlation between age, body mass index, lung function, and IgE variability. Greater variability was associated with female gender (p = .06). There was no association with peripheral eosinophilia, systemic corticosteroid use, and leukotriene modifier use at presentation. The observed variability would have affected omalizumab dosing in 20 out of 42 patients. Six patients who may have qualified at different time points would not have been deemed candidates based on an IgE concentration <30 IU/ml or >700 IU/ml. CONCLUSION Serum IgE concentration may have clinically significant variability over time, affecting candidacy and dosing of omalizumab. Our findings imply that repeating serum IgE determinations merits consideration for patients whose initial concentrations are <30 or >700 IU/ml. Prospective studies are warranted to delineate the factors that contribute to IgE variability.