Candida albicans is no longer the only yeast involved in infectious disorders, as others, such as C. famata, commonly associated with foods as well as terrestrial and marine environments, are being recognized as potential emerging pathogens that cause human candidiasis. We investigated the interaction between C. famata and human epithelial cells using monolayer cultures and an engineered human oral mucosa (EHOM). C. famata was able to adhere to gingival epithelial cells but failed to adopt the hyphal form in the presence/absence of proteins. Interestingly, when cultured onto the engineered human oral mucosa (EHOM), C. famata formed a biofilm and invaded the connective tissue. When normal human gingival epithelial cells were put in contact with C. famata, they expressed high levels of Toll-like receptors (TLR)-2, -4, and -6, but not TLR-9 mARN. The upregulation of TLRs was paralleled by an increase of IL-1beta and TNFalpha, but not IFNgamma mARN expression, suggesting the involvement of specific pro-inflammatory cytokines (IL-1beta and TNFalpha) in the defense against infection with C. famata. The active role of epithelial cells in the innate immunity against C. famata infection was enhanced by their capacity to express high levels of human beta-defensin (HBD)-1, -2, and -3. The upregulation of pro-inflammatory cytokines and antimicrobial peptide expression may explain the growth inhibition of C. famata by the gingival epithelial cells. Overall results provide additional evidence of the involvement of C. famata in the activation of innate immunity and the contribution of human epithelial cells in local defenses against such exogenous stimulations as C. famata infections.