Objectives: To explore associations between clinical signs of stomatitis and tissue/denture infection, as well as salivary and serum biomarkers. Methods: An IRB approved, case-control study enrolled 32 edentate subjects, 17 with healthy palatal mucosa as controls and 15 with denture stomatitis (DS) (Newton's classification type II and III). Rate of salivary flow, exfoliative cytology, culture, salivary cytokines levels, serum C-reactive protein levels, and DNA-DNA checkerboard analyses were performed. Results: denture levels of yeast were higher and more strongly predictive of clinical DS than salivary or mucosal levels. Certain pro-inflammatory cytokines levels were increased in DS and associated with counts of C. albicans in saliva. Conclusions: the denture, rather than the inflamed palatal mucosa, is the primary C. albicans habitat. At this point, data suggest no evidence that DS can induce systemic inflammation.