Oropharyngeal candidiasis (OPC) is the most common opportunistic infection in immunosuppressed patients. In OPC, Candida albicans persists intraepithelially triggering inflammatory events, without generally causing invasive infection. Since neutrophils play an important role in preventing invasive infection and since they establish contact with the microorganisms only within the epithelial cell layer, we examined the ability of Candida-infected oral epithelial cells to augment neutrophil-mediated hyphal damage in vitro. We found that challenge of neutrophils with hyphal organisms in the presence of C. albicans-infected oral epithelial cell supernatants resulted in a significantly greater suppression of hyphal cell metabolic activity compared to basal neutrophil anti-fungal function. Anti-hyphal activity in response to these supernatants was partly inhibited by neutralizing anti-IL-1alpha antibody and IL-1 receptor antagonist. Control supernatants from uninfected oral epithelial cells, as well as C. albicans conditioned-medium had a much less pronounced effect on neutrophil anti-fungal activity, which was not inhibited by these cytokine antagonists. We conclude that oral epithelial cells can act as activators of neutrophil anti-hyphal function, an effect that can be partly attributed to the generation of immunomodulatory cytokines during the interaction of oral mucosal cells with the pathogen.