Alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuropeptide predominantly produced by the pituitary gland, but it is also generated by many extra-pituitary cells including keratinocytes of the skin. This neuropeptide has anti-inflammatory and antimicrobial effects and probably contributes in innate immunity. Staphylococcus aureus is the aetiological agent of a wide range of infections in humans. Colonization of human skin by S. aureus is a characteristic feature of several skin diseases and is often followed by tissue invasion and severe cell damage. The aim of our study was to detect a possible role of alpha-MSH during the early infection stages in the adhesion and penetration of keratinocytes before cell damage. Our data demonstrated that alpha-MSH precociously down-regulates the production of integrins such as beta1 and heat shock surface protein 70, essential molecules for the entry of S. aureus. Moreover, in our experimental model, alpha-MSH induces the down-regulation of the pro-inflammatory cytokine expression and of the adhesion molecules in keratinocytes activated by S. aureus. Our data suggest that alpha-MSH plays a protective role in the skin by reducing infection and the inflammatory process.