Secreted aspartic proteinases (Saps) encoded by 10 genes of Candida albicans are important virulence factors for different types of candidiasis. Distinct SAP genes have previously been shown to contribute to tissue damage in a model of oral candidiasis. In this study a progressive SAP expression in the order SAP1 and SAP2 > SAP8 > SAP6 > SAP3 was observed in an in vitro model of cutaneous candidiasis based on reconstituted human epidermis. Transcripts of SAP1 and SAP2 were detected during initial invasion of the stratum corneum by C. albicans. Deeper, extensive penetration of the corneal layer was accompanied by additional SAP8 mRNA. SAP6 expression occurred concomitantly with germ tube formation and extensive hyphal growth in the strata granulosum, spinosum, and basale. Ultrastructural studies using specific polyclonal antibodies directed against the gene products of SAP1-3 and SAP4-6 revealed predominant expression of Sap1-3. The protective effect of the aspartic proteinase inhibitor pepstatin A during infection of the epidermis and an attenuated virulence phenotype of SAP-deficient mutants suggest that the observed SAP expression correlates with tissue damage in the skin.