Oral epithelium reacts to microbial challenges by eliciting a defensive response that includes the production of antimicrobial peptides. This study investigated the expression of human beta-defensins-1, 2, and 3 in reconstituted human oral epithelia during experimental oral infections with six different Candida species, and a wild-type C. albicans isolate and five of its mutants. The expression of defensins was induced after 12 hours infection with the wild-type C. albicans, but this response was not seen for the noninvasive hyphal mutants nor the secreted aspartyl proteinase mutants. Furthermore, defensin expression was not detected after 48 hours in epithelia infected with either C. albicans wild-type isolate or its invasive hyphal and proteinase mutants. Most of the non-albicans Candida were capable of inducing the expression of defensins in epithelia after 24 or 48 hours of infection. These Candida-host interaction patterns suggest that the oral epithelia possess mechanisms for sensing the early invasion of C. albicans through recognition of the presence of hyphae and proteinases of Candida and respond to the insult by producing antimicrobial peptides. This hyphal-invasion-dependent inhibition of defensin expression in oral epithelium that undermines the host surveillance system represents a hitherto undescribed novel pathogenic mechanism of C. albicans.