alpha-Melanocyte stimulating hormone (alpha-MSH) is an endogenous linear tridecapeptide with potent antiinflammatory effects. We recently demonstrated that alpha-MSH and its C-terminal sequence Lys-Pro-Val (alpha-MSH (11-13)) have antimicrobial effects against two major and representative pathogens: Staphylococcus aureus and Candida albicans. In an attempt to improve the candidacidal activity of alpha-MSH and to better understand the peptide structure-antifungal activity relations, we designed and synthesized novel peptide analogues. Because previous data suggested that antimicrobial effects of alpha-MSH were receptor-mediated, we chose to focus on the sequence alpha-MSH (6-13), which contains the invariant core sequence His-Phe-Arg-Trp (6-9) that is important for binding to the known melanocortin receptors and also contains the sequence Lys-Pro-Val (11-13) that is known to be important for antimicrobial activity. In this structure-activity study, we discovered several compounds that have greater candidacidal activity than alpha-MSH. The peptide [d-Nal-7,Phe-12]-alpha-MSH (6-13) was the most potent of the analogues tested. The present results are very encouraging because they show the great potential of these peptides as a truly novel class of candidacidal compounds.