Oral epithelial cells significantly influence host inflammatory responses against Candida albicans in oropharyngeal candidiasis. We sought to elucidate the pattern of interleukin-8 (IL-8) expression by oral epithelial cells, which may function as an early innate immune system mediator during C. albicans infection. Primary human gingival epithelial cells (HGECs) were co-cultured with either viable or heat-killed C. albicans or fungal-derived substances, such as fungal secretion, fungal extracted proteins, and alpha-mannan. In vitro cell injury due to viable C. albicans was detectable by an adenosine triphosphate-based assay after 12h of infection. Prior to the detection of cell injury, HGECs clearly increased production of interleukin-1 alpha (IL-1alpha) and IL-8 in response to C. albicans infection, as determined by enzyme-linked immunosorbent assay and real-time reverse transcription PCR. High concentrations of a suspension of heat-killed yeast and all fungal-derived substances examined also stimulated IL-8 production by HGECs. Incubation with neutralizing anti-IL-1alpha or anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibodies (mAb) significantly inhibited C. albicans-induced IL-8 production. Use of mAbs against both IL-1alpha and ICAM-1 produced a more significant combined inhibitory effect on the IL-8 production than either mAb alone. These findings indicate that HGECs synthesize increased levels of IL-1alpha and IL-8 in response to viable C. albicans before cell injury is manifested. Fungal cell-wall components, alpha-mannan, and fungal protein extracts are all sufficient to increase IL-8 production. The molecular mechanisms governing the IL-8 response of HGECs to C. albicans infection likely involve multiple converging signal transduction pathways, including those mediated by IL-1alpha and ICAM-1 activation.