I n humans, hereditary inactivation of either p22^phox or gp91^phox leads to chronic granulomatous disease (CGD), a severe immune disorder characterized by the inability of phagocytes to produce bacteria-destroying ROS. Heterodimers of p22^phox and gp91^phox proteins constitute the superoxide-producing cytochrome core of the phagocyte NADPH oxidase. In this study, we identified the nmf333 mouse strain as what we believe to be the first animal model of p22^phox deficiency. Characterization of nmf333 mice revealed that deletion of p22^phox inactivated not only the phagocyte NADPH oxidase, but also a second cytochrome in the inner ear epithelium. As a consequence, mice of the nmf333 strain exhibit a compound phenotype consisting of both a CGD-like immune defect and a balance disorder caused by the aberrant development of gravity-sensing organs. Thus, in addition to identifying a model of p22^phox-dependent immune deficiency, our study indicates that a clinically identifiable patient population with an otherwise cryptic loss of gravity-sensor function may exist. Thus, p22^phox represents a shared and essential component of at least 2 superoxide-producing cytochromes with entirely different biological functions. The site of p22^phox expression in the inner ear leads us to propose what we believe to be a novel mechanism for the control of vestibular organogenesis.