Background: Secretory leukocyte protease inhibitor (SLPI) exhibits antimicrobial activities that, in addition to other well-characterized proteins such as lysozyme and lactoferrin, is thought to play a critical role in mucosal defenses. Although elderly individuals are particularly susceptible to mucosal infections, salivary production of SLPI has not been assessed in an aged cohort. Objectives: Hypothesizing that oral SLPI concentrations are reduced with advanced age, this cross-sectional study compared SLPI concentrations to concentrations of lysozyme, lactoferrin and total protein in unstimulated salivary secretions of healthy, community-dwelling 79+-year-old and younger adults. Methods: Study participants were 45 non-hospitalized dentate adults aged 79–89 (23 elderly) or 21–51 years (22 non-elderly). Home-based interviews and clinical examinations determined dentate status and confirmed the absence of dentures, oral mucosal disease, anti-infective medication use, irradiation therapy for head and neck cancer and self-perceived xerostomia. Whole unstimulated saliva was collected from all subjects and analyzed for antimicrobial protein concentration by enzyme-linked immunosorbent assay and for total protein content by the bicinchoninic acid method. Bivariate and multivariate (generalized linear modeling) analyses evaluated the relationships between age, gender and salivary protein concentrations. Results: Mean salivary levels of SLPI and lysozyme were lower in elderly compared with non-elderly subjects (p < 0.001), unlike lactoferrin and total protein levels. Similar results were obtained when concentrations of the individual proteins were normalized to the total protein concentration, suggesting that glandular production of SLPI and lysozyme preferentially decreases with aging. Gender differences were detected only for SLPI concentrations; males had lower SLPI levels than females regardless of age (p < 0.01). Generalized linear models confirmed that age (p < 0.001) and gender (p < 0.05) were each associated with the SLPI concentration and together accounted for 50% of the variation in SLPI concentration in this population. Conclusion: These findings indicate that SLPI production is diminished among healthy community-dwelling older adults, particularly elderly males. Further investigation should determine the impact of decreased local SLPI production on the increased risk of oral mucosal disease with advanced age.