DiGeorge syndrome (DGS) is a primary immunodeficiency disease characterized by multiple clinical features, including congenital heart defects, typical facial appearance, hypocalcemia, and immunodeficiency associated to thymic hypoplasia. A subset of patients with DGS may also have contemporary allergic diseases, possibly in the context of T cell dysregulation. Our work presents an unusual case of DGS in coincidence with severe allergic asthma successfully treated by humanized monoclonal anti-IgE antibody, omalizumab. Biological therapy with omalizumab is indicated as an add-on treatment for poorly controlled asthma in patients with severe persistent allergic asthma aged 6 years and above, who meet strict criteria. While data available from clinical trials suggest that omalizumab is generally well-tolerated, a little is known about its efficacy and tolerability in the context of underlying immunodeficiency. We reported for the first time that omalizumab could be safely effective in treatment of severe allergic asthma in patients with DGS, without modification of immunological parameters.