Periodontitis is a biofilm-induced chronic inflammatory disease that causes gingival inflammation and attachment loss. Destruction of periodontal tissue is a consequence of host immune inflammatory responses induced by periodontal microorganisms. Wnt5a is strongly associated with inflammatory responses and shown by several studies to be involved in inflammatory diseases including periodontitis. sFRP5 is a homolog of Wnt5a receptor, frizzled protein. sFRP5 is a known inhibitor of Wnt5a signaling. To investigate the correlation of Wnt5a and sFRP5 in periodontitis and healthy tissues, experiments were set up using both clinical specimens and further investigation with stimulations of human gingival epithelial cells (HGECs). Wnt5a and sFRP5 mRNA expression and protein levels were studied by immunohistochemistry, quantitative real time PCR, and ELISA. Results showed localization of Wnt5a and sFRP5 in periodontal tissue and higher level of Wnt5a expression in periodontitis group than in healthy group and vice versa for sFRP5 expression. LPS from P. gingivalis or E. coli induced Wnt5a expression and reduced sFRP5 expression. Moreover, sFRP5 mediated anti-inflammatory effects by inhibiting IL-8 production in HGECs. In conclusion, inverse correlation of Wnt5a and sFRP5 expression was shown for the first time and human gingival epithelial cells were also proved to express both Wnt5a and sFRP5. Wnt5a appears to be an important target for intervention in periodontitis and sFRP5 is likely a promising therapeutic compound.