Oropharyngeal candidiasis (OPC), caused primarily by Candida albicans, is the most common oral infection in HIV⁺ persons. Although Th1-type CD4⁺ T cells are the predominant host defense mechanism against OPC, CD8⁺ T cells and epithelial cells become important when blood CD4⁺ T cells are reduced below a protective threshold during progression to AIDS. In an early cross-sectional study, OPC⁺ tissue biopsied from HIV⁺ persons had an accumulation of activated memory CD8⁺ T cells at the oral epithelial–lamina propria interface, with reduced expression of the adhesion molecule E-cadherin, suggesting a protective role for CD8⁺ T cells but a dysfunction in the mucosal migration of the cells. In a subsequent 1-year longitudinal study, OPC⁻ patients with high oral Candida colonization (indicative of a preclinical OPC condition), had higher numbers of CD8⁺ T cells distributed throughout the tissue, with normal E-cadherin expression. In OPC⁺ patients, where lack of CD8⁺ T cell migration was associated with reduced E-cadherin, subsequent evaluations following successful treatment of infection revealed normal E-cadherin expression and cellular distribution. Regarding epithelial cell responses, intact oral epithelial cells exhibit fungistatic activity via an acid-labile protein moiety. A proteomic analysis revealed that annexin A1 is a strong candidate for the effector moiety. The current hypothesis is that under reduced CD4⁺ T cells, HIV⁺ persons protected from OPC have CD8⁺ T cells that migrate to the site of a preclinical infection under normal expression of E-cadherin, whereas those with OPC have a transient reduction in E-cadherin that prohibits CD8⁺ T cells from migrating for effector function. Oral epithelial cells concomitantly function through annexin A1 to keep Candida in a commensal state but can easily be overwhelmed, thereby contributing to susceptibility to OPC.