HIV-infected individuals constitute a population highly susceptible to opportunistic infections particularly oral candidiasis (OC) caused by the most pathogenic human fungal species Candida albicans. The susceptibility to OC is enhanced under reduced CD4+ T-cells however local host defenses may also play a key role. Host-produced salivary antimicrobial peptides are considered to be an important part of the host innate immune system involved in protection of the oral cavity against colonization and infection by microbial species. Histatin-5 (Hst-5) specifically has exhibited potent anti-candidal properties in vitro. However, its importance in protecting the oral mucosa against candidal colonization and importantly, its contribution to the observed enhanced susceptibility of HIV+ individuals to candidiasis has not been previously investigated most likely due to the lack of feasible and sensitive methods for measuring salivary Hst-5 concentrations. To that end, the goal of this study was to develop a novel immunoassay to accurately measure and analyze salivary Hst-5 levels within the context of HIV infection and oral candidal colonization in order to validate the hypothesis that salivary Hst-5 levels are compromised in HIV+ individuals. The results from these studies demonstrated that salivary Hst-5 levels are significantly (60%) decreased in HIV+ individuals compared to healthy subjects concomitant with enhanced candidal prevalence. The findings generated from this project provided new insights into oral innate immune defense mechanisms and the enhanced susceptibility of HIV+ individuals to oral candidiasis.