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ABSTRACTStaphylococcus aureusnasal carriage is a common condition affecting both healthy and immunocompromised populations and provides a reservoir for dissemination of potentially infectious strains by casual contact. The factors regulating the onset and duration of nasal S. aureuscolonization are mostly unknown, and a human-relevant animal model is needed. Here, we screened 17 pig-tailed macaques (Macaca nemestrina) for S. aureuscarriage, and 14 of 17 animals tested positive in the nose at one or both screening sessions (8 weeks apart), while the other 3 animals were negative in the nose but positive in the pharynx at least once. As in humans, S. aureuscolonization was densest in the nose, and treatment of the nostrils with mupirocin ointment effectively cleared the nostrils and 6 extranasal body sites. Experimental nasal S. aureuscolonization was established with 104CFU/nostril, and both autologous and nonautologous strains survived over 40 days without any apparent adverse effects. A human nasal S. aureusisolate (strain D579, sequence type 398) was carried in 4 of 6 animals for over 3 weeks. Nostrils that did eradicate experimentally applied S. aureusexhibited neutrophilic innate immunity marked by elevated nasal interleukin-1β (IL-1β), IL-8, and monocyte chemotactic protein 1 levels and a 10-fold decreased IL-1 receptor antagonist/IL-1β ratio within 7 days postinoculation, analogous to the human condition. Taken together, pig-tailed macaques represent a physiological model of human S. aureusnasal carriage that may be utilized for testing natural colonization and decolonization mechanisms as well as novel classes of anti-S. aureustherapeutics.