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Background. Staphylococcus aureus nasal carriage is influenced by multifactorial interactions which are difficult to study in open populations. Therefore, we concomitantly assessed the epidemiological, microbiological, and human-genetic carriage-related factors in a nearly closed population. Methods. In 2006 and 2008, we collected nasal S. aureus strains, human DNA, and epidemiological data from 154 adult Wayampi Amerindians living in an isolated village in the Amazonian forest. The genetics of the strains (multilocus sequence type, spa type, and toxin-content type), epidemiological risk factors, antibiotic exposure, and allelic polymorphism of human genes putatively involved in carriage of the persistent carriers were compared with those of other volunteers. Results. Overall carriage prevalence was 41.7% in 2006 and 57.8% in 2008, but the overall prevalence of persistent carriage was only 26%. The rare and phylogenetically distant multilocus sequence type ST1223 was present in 18.5% of the carriers in 2006 and 34.8% in 2008. No epidemiological factors or antibiotic exposure were significantly associated with persistent carriage, but single nucleotide polymorphism distribution in C-reactive proteins C2042T and C1184T and interleukin-4 C524T genes was significantly associated (P =.02, by global test). Conclusion. Host genetic factors appeared to be the predominant determinant for S. aureus persistent nasal carriage in humans. [ABSTRACT FROM AUTHOR]