Background: Eosinophil-associated gastrointestinal disorders (EGIDs) are commonly associated with atopy and are being recognized with increasing frequency. Current therapy for EGIDs is inadequate. Objective: We sought to determine the efficacy of anti-IgE therapy in EGIDs and investigate the role of IgE in disease pathogenesis. Methods: Nine subjects with EGIDs received omalizumab every 2 weeks for 16 weeks while other therapy was held constant. Blood absolute eosinophil counts, tissue eosinophil counts, symptom scores, and free IgE levels were serially measured. Allergen skin testing and flow cytometry for basophil activation and FcεRI were determined at baseline and at week 16. Results: Omalizumab was associated with a decrease in absolute eosinophil count at both the week 16 (34%, P = .004) and combined weeks 12 to 16 (42%, P = .012) time points. Tissue eosinophils decreased in the duodenum (59%) and gastric antrum (69%) but did not reach statistical significance (P = .074 and .098, respectively). Esophageal eosinophil counts remained unchanged. Basophil and dendritic cell FcεRI expression and free IgE levels were all significantly decreased (P < .005). Omalizumab increased the concentration of allergen required to trigger half-maximal basophil activation by 170-fold. Allergen skin test wheal and erythema responses decreased by 78% and 82%, respectively. Symptom scores were decreased at both the midstudy (63%) and end of study (70%) time points (P < .005 for both). Conclusion: These results demonstrate that IgE-mediated processes contribute to the generation of eosinophilic inflammation in EGIDs and suggest that anti-IgE therapy might be effective in these disorders. Clinical implications: Anti-IgE might be a potential therapy for EGIDs. © 2007 American Academy of Allergy, Asthma & Immunology.