Updated project metadata. Best known for their roles in allergic diseases, the physiologic function of immunoglobulin E (IgE) and mast cells (the so-called allergy module of immunity) has been enigmatic. Recent evidence shows that allergic reactions can help to protect against the toxicity of venoms. As bacteria are a potent alternative source of toxins, we assessed the potential role of the allergy module in antibacterial host defense. We observed that the immune response against S. aureus skin infection includes specific IgEs and substantially improves systemic host defense against secondary S. aureus infections in mice. This acquired protection depends on functional IgE effector mechanisms and mast cells. Our results reveal the powerful antibacterial potential of the allergy module and therefore a novel physiologic function of IgEs and mast cells.