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Background. Staphylococcus aureus infections of the skin are a public health problem of growing importance. Antimicrobial peptides in human skin are believed to play an important role in innate defense against intruding pathogens. This study aimed to clarify whether their baseline expression influences the propensity of healthy individuals to develop S. aureus-positive skin infections. Methods. Using real-time polymerase chain reaction technique and a prospective case-control design, we determined the expression of messenger RNA coding for human β-defensin 2 and 3 as well as RNase 7 in unaffected skin of 20 travelers returning with Staphylococcus aureus-positive skin infection (case patients) relative to levels in 40 matched control subjects. Results. Expression of RNase 7 was found to be 64% higher in unaffected skin of control subjects, compared with unaffected skin of case patients (95% confidence interval, 17%-131%; P = .007). This association remained stable after controlling for S. aureus nasal carriage, smoking, level of accommodation, and history of allergy. No such association was present for human β-defensin 2 or 3. Conclusions. In conjunction with the existing evidence from in vitro studies, these findings suggest that antimicrobial peptides found at high baseline levels in healthy skin, such as RNase 7, confer protection against S. aureus infection of the skin. [ABSTRACT FROM AUTHOR]