Background: Interferon-α (IFN-α) production in humans is an early event in the nonspecific cellular response to viruses and mediates a wide range of antiviral and immunoregulatory activities. Little is known about the role of IFN-α in allergic disease. Methods: In the present study, we performed a retrospective comparative analysis of 88 children with and without an atopic phenotype for virus-induced IFN-α production in blood cultures. Results: We were able to demonstrate that patients with allergic asthma (aA) produced significantly lower amounts of virus-induced IFN-α than healthy children and patients with nonallergic asthma (naA). Furthermore, the number of eosinophils in atopic children as a marker for allergic inflammation correlated negatively with the IFN-α level in blood cultures. Additionally, we found differences between aA and naA patients with respect to the capacity to produce IFN-γ. Although atopy is thought to be associated with a Th2 cytokine response, in our study, IFN-γ release was not reduced in the allergic children. In contrast, patients with allergic rhinitis showed a significant increase in IFN-γ release compared to naA patients. Conclusions: In our study, an early atopic phenotype was related to a reduction in virus induced IFN-α release from blood cultures. Thus, after further prospective evaluation, the IFN-α level may serve as an additional in vitro marker for the definition of atopy in children.