Purpose: Bisphosphonate (BP)-associated osteonecrosis of the jaw (BON) lacks a defined pathophysiologic mechanism and treatment regimen. This current study was designed to be part of a parent BON pathogenesis series of protocols to investigate the contributing factors of causation. The following hypothesis was tested: Subjects receiving long term bisphosphonate therapy that have developed BON have a more acidic oral environment i.e. as measured by salivary pH than normal (no BP exposure) subjects and those receiving long term bisphosphonate therapy that have not developed BON. This study assessed the pH of saliva in subjects receiving long term bisphosphonate therapy so that possible oral buffers could eventually be developed and investigated as possible treatments i.e. to reduce the acidic effects BPs such as zoledronic acid (ZA) have in BON wound healing. Methods: Using the fully IRB approved HIPAA partial waiver for recruitment, subjects were selected based on history and physical examination in order to document previous and/or current use of bisphosphonates. Standard of care physical examination was used to determine the presence or absence of BON lesions intraorally. As part of a fully IRB approved protocol the informed consent process was used and for those willing to participate and having signed the consent document, we collected the single sample of saliva. We employed these ex-vivo studies using pH measurement on ~5 ml of fresh unstimulated whole saliva collected over a 5 minute time period at this single visit. Results: Ex-vivo, we have shown in this study that patients with active lesions of BON have more acidic saliva as compared to those without BON or in those not taking a BP. Conclusion: These findings suggest that acidic salivary pH is directly associated with BON, may play a role in the initiation and prolongation of oral BON and may eventually support the potential role of using salivary buffers to offset acidic saliva as an adjunct therapeutic treatment for BON, specifically to speed wound healing.