LGR5 is pivotal to oral cavity development and is implicated in epithelial malignancy whereby stimulation of LGR5 potentiates canonical Wnt signaling. This investigation tested our hypothesis of a correlation between LGR5 expression and the severity of oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC).Immunoreactive LGR5 protein expression was quantified in 342 tissue samples ranging in disease severity from normal through mild and moderate or severe OED to OSCC.LGR5 was restricted to the basal layers for normal tissues, projected to the stratum granulosum in severe dysplasia, intense in carcinoma nests of well-differentiated OSCC, but uniformly diffuse throughout poorly differentiated OSCC. Median LGR5 immunoreactivity index scores increased with disease severity: mild dysplasia = 1 < moderate or severe dysplasia = 2.5 < OSCC = 6.Inclusion of LGR5 in a panel of immunohistochemical biomarkers may improve identification of increased potential for malignancy in OED.