CD14 is a co-receptor involved in the recognition of Gram-negative and Gram-positive bacteria, the latter known to cause dental caries. The aim of this study was to determine whether soluble CD14 (sCD14) in saliva was associated with caries activity and the collection method from the saliva. The study included 55 participants aged 20 to 40 years, 30 with dental caries and 25 caries-free controls. We collected 110 saliva samples in total, 55 of resting saliva and 55 of mechanically stimulated saliva. Median levels of sCD14, measured with a matrix-matched enzyme-linked immunosorbent assay (ELISA), were higher in the caries-active than in the caries-free group in either resting (203.3 vs.167.9 ng mL ; P<0.01). Hyposalivation was observed only in the caries-active group (10 and 13 % in stimulated and resting saliva, respectively). Higher salivary sCD14 levels and secretion rates were clearly associated with dental caries and resting saliva. Future studies should focus on the clinical utility of salivary sCD14 as a potential biomarker and predictor of future caries events.