BACKGROUND: Perennial aeroallergen sensitization is associated with greater asthma morbidity and is required for treatment with omalizumab. OBJECTIVE: To investigate the predictive relationship between the number of aeroallergen sensitizations, total serum IgE, and serum eosinophil count, and response to omalizumab in children and adolescents with asthma treated during the fall season. METHODS: This analysis includes inner-city patients with persistent asthma and recent exacerbations aged 6-20 years comprising the placebo and omalizumab-treated groups in two completed randomized clinical trials, the Inner-City Anti-IgE Therapy for Asthma (ICATA) study and the Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations (PROSE) study. Logistic regression modeled the relationship between greater degrees of markers of allergic inflammation and the primary outcome of fall season asthma exacerbations. RESULTS: The analysis included 761 participants who were 62% male and 59% African American with a median age of 10 years. Fall asthma exacerbations were significantly higher in children with greater numbers of aeroallergen-specific sensitizations in the placebo group (OR 1.33, 95% CI 1.11-1.60, p<0.01), but not in the omalizumab-treated children (OR 1.08, 95% CI 0.91-1.28, p=0.37) indicating a significant differential effect (p<0.01). Likewise, there was a differential effect of omalizumab treatment in children with greater baseline total serum IgE levels (p<0.01) or greater baseline serum eosinophil counts (p<0.01). Multiple aeroallergen sensitization was the best predictor of response to omalizumab; treated participants sensitized to ≥4 different groups of aeroallergens had a 51% reduction in the odds of a fall exacerbation (OR 0.49, 95% CI 0.30-0.81, p<0.01). CONCLUSIONS: In preventing fall season asthma exacerbations, treatment with omalizumab was most beneficial in children with a greater degree of allergic inflammation.