RATIONALE: Allergic inflammation has been linked to increased susceptibility to viral illnesses, but it is unclear whether this association is causal. OBJECTIVE: To test whether omalizumab treatment to reduce IgE would shorten the frequency and duration of rhinovirus illnesses in children with allergic asthma. METHODS: The Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations (PROSE) was a study of children with allergic asthma (6-17 years, n=478) from low-income census tracts in 8 U.S. cities, and we analyzed virology for the groups randomized to treatment with guidelines-based asthma care (n=89) or add-on omalizumab (n=259). Weekly nasal mucus samples were analyzed for rhinoviruses, and respiratory symptoms and asthma exacerbations were recorded over a 90-day period during the fall seasons of 2012 or 2013. Adjusted illness rates (illnesses per sample) by treatment arm were calculated using a Poisson regression. MEASUREMENTS AND MAIN RESULTS: Rhinoviruses were detected in 97/171 (57%) exacerbation samples and 2,150/5,959 (36%) non-exacerbation samples (OR=2.32, p<0.001). Exacerbations were significantly associated with detection of rhinovirus-C (OR=2.85, p<0.001) and rhinovirus-A (OR=2.92, p<0.001), and to a lesser extent, rhinovirus-B (OR=1.98, p=0.019). Omalizumab decreased the duration of RV infection (11.2 days vs 12.4 days, p=0.03), and reduced peak rhinovirus shedding by 0.4 log units (95% CI -0.77, -0.02, p=0.04). Finally, omalizumab decreased the frequency of rhinovirus illnesses (Risk Ratio [RR] 0.64, 95% CI 0.49-0.84). CONCLUSIONS: In children with allergic asthma, treatment with omalizumab decreased the duration of RV infections, viral shedding, and the risk of RV illnesses. These findings provide direct evidence that blocking IgE decreases susceptibility to RV infections and illness. Clinical trial registration available at www.clinicaltrials.gov, ID NCT0143040.