BACKGROUND: Atopy and viral respiratory tract infections synergistically promote asthma exacerbations. IgE cross-linking inhibits critical virus-induced IFN-alpha responses of plasmacytoid dendritic cells (pDCs), which can be deficient in patients with allergic asthma. OBJECTIVE: We sought to determine whether reducing IgE levels in vivo with omalizumab treatment increases pDC antiviral IFN-alpha responses in inner-city children with asthma. METHODS: PBMCs and pDCs isolated from children with exacerbation-prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross-linking. IFN-alpha levels were measured in supernatants, and mRNA expression of IFN-alpha pathway genes was determined by using quantitative RT-PCR (qRT-PCR) in cell pellets. FcepsilonRIalpha protein levels and mRNA expression were measured in unstimulated cells by using flow cytometry and qRT-PCR, respectively. Changes in these outcomes and associations with clinical outcomes were analyzed, and statistical modeling was used to identify risk factors for asthma exacerbations. RESULTS: Omalizumab treatment increased rhinovirus- and influenza-induced PBMC and rhinovirus-induced pDC IFN-alpha responses in the presence of IgE cross-linking and reduced pDC surface FcepsilonRIalpha expression. Omalizumab-induced reductions in pDC FcepsilonRIalpha levels were significantly associated with a lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFN-alpha responses. PBMC FcepsilonRIalpha mRNA expression measured on study entry significantly improved an existing model of exacerbation prediction. CONCLUSIONS: These findings indicate that omalizumab treatment augments pDC IFN-alpha responses and attenuates pDC FcepsilonRIalpha protein expression and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus-induced asthma exacerbations.