Lipopolysaccharide (LPS) binds to soluble (s)CD14. We investigated which factors contribute to variations in sCD14 levels in periodontitis, a chronic infectious disease of tooth-supporting tissues associated with endotoxemia and leading to inflammation and subsequently loss of teeth. The sCD14 levels were determined by ELISA in healthy controls (n=57) and untreated patients (59 moderate and 46 severe) and their relation with markers of systemic inflammation (C-reactive protein levels, and leukocyte, neutrophil and lymphocyte counts) was assessed. Anti-Aggregatibacter actinomycetemcomitans and anti-Porphyromonas gingivalis IgG levels were established by ELISA and CD14(-260) genotype was determined in a TaqMan allelic discrimination assay. Increased levels of sCD14 were more frequent among periodontitis patients (P=0.026) and showed a severity-dependence with increasing levels of periodontal breakdown (P=0.008). In patients, levels of sCD14 correlated positively with CRP (P=0.043), leukocyte numbers (P=0.011) and negatively with anti-A. actinomycetemcomitans IgG (P=0.007). In a multivariate analysis, sCD14 levels were predicted by ethnicity, age, educational level, and in Caucasian subjects also by the severity of periodontal destruction, but not by anti-P. gingivalis IgG or the CD14(-260) genotype. Periodontitis is associated with elevated levels of sCD14.