<jats:title>ABSTRACT</jats:title> <jats:p> <jats:named-content content-type="genus-species">Porphyromonas gingivalis</jats:named-content> is an established pathogen in periodontal disease and an emerging pathogen in serious systemic conditions, including some forms of cancer. We investigated the effect of <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> on β-catenin signaling, a major pathway in the control of cell proliferation and tumorigenesis. Infection of gingival epithelial cells with <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> did not influence the phosphorylation status of β-catenin but resulted in proteolytic processing. The use of mutants deficient in gingipain production, along with gingipain-specific inhibitors, revealed that gingipain proteolytic activity was required for β-catenin processing. The β-catenin destruction complex components Axin1, adenomatous polyposis coli (APC), and GSK3β were also proteolytically processed by <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> gingipains. Cell fractionation and Western blotting demonstrated that β-catenin fragments were translocated to the nucleus. The accumulation of β-catenin in the nucleus following <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> infection was confirmed by immunofluorescence microscopy. A luciferase reporter assay showed that <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> increased the activity of the β-catenin-dependent TCF/LEF promoter. <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> did not increase Wnt3a mRNA levels, a finding consistent with <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> -induced proteolytic processing causing the increase in TCF/LEF promoter activity. Thus, our data indicate that <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> can induce the noncanonical activation of β-catenin and disassociation of the β-catenin destruction complex by gingipain-dependent proteolytic processing. β-Catenin activation in epithelial cells by <jats:named-content content-type="genus-species">P. gingivalis</jats:named-content> may contribute to a proliferative phenotype. </jats:p>