Neutrophils are central effector cells in innate immune defense and their timely arrival leads to death of invading microbes within hours of infection. Defects in the generation or function of neutrophils are predisposing risk factors for life-threatening infections. Antimicrobials, key components of the bactericidal arsenal, are known to originate from cells of innate immunity, including those of neutrophils and macrophages. In the epithelia of the intestinal tract and the airway, these peptides also reside and participate in host defense by keeping commensals in check, as well as protecting from environmentally introduced microbes. Here we describe functional characterization of a novel protein termed ONZIN, whose expression profile, mimicking that of an antimicrobial, is consistent with a role in immune defense mechanisms. While neutrophils deficient in ONZIN appear to have normal chemotaxis, phagocytosis, and oxidative burst, they are unable to efficiently eliminate microbes. To better understand the functional activity of ONZIN, recombinant proteins were produced. Although the recombinant ONZIN did not display direct antimicrobial activity, studies with ONZIN deficient mice demonstrate that ONZIN is necessary in neutrophils for optimal intracellular killing of bacteria. Further studies, examining the role of ONZIN in atopic diseases, suggested that ONZIN is also required for development of a normal T cell response in mice. Taken together, these studies support a role for ONZIN in immune defense, not only for the innate immune response mediated by phagocytes but also for mounting an adaptive immune response mediated by T cells.