OBJECTIVE Parathyroid hormone-related protein (PTHrP) production has been demonstrated in a variety of tumor subtypes. Local production of PTHrP by metastatic tumor cells in bone has been linked to bone destruction and tumor growth. Ameloblastoma (AB) is a relatively common odontogenic epithelial neoplasm that manifests local infiltrative intraosseous growth. AB recapitulates the developing enamel epithelium, in which PTHrP recently has been demonstrated. Yet PTHrP expression in a series of ABs has not been studied to date. The purpose of this investigation is to assess the expression of PTHrP in ameloblastoma. METHODS Formalin-fixed, paraffin-embedded tissue sections of ameloblastoma (n = 30; 24 conventional, 4 unicystic, and 2 arising in dentigerous cyst) were immunostained with anti-PTHrP antibody using a multistep streptavidin-peroxidase technique. Semiquantitative scoring of immunoreactivity was assessed as mild, moderate, and intense. RESULTS All cases (100%) demonstrated positive immunoreactivity, with mild reaction in 3 conventional ABs, 1 unicystic and 1 AB arising in dentigerous cyst, and with moderate reaction in 12 conventional ABs, 3 unicystic and 1 AB arising in dentigerous cyst. Intense immunoreactivity was seen in 9 cases of conventional AB. This difference in immunostaining was not statistically significant (Sigma2 = 4.41, df = 4, P = .358). CONCLUSIONS The results of this investigation suggest that PTHrP may play a significant role in local bone resorption, offering at least partial explanation for the tumor's infiltrative growth and destructive behavior. The uniformity of PTHrP expression by AB, as detailed in this study, may harbor significant therapeutic implications, particularly through PTHrP-blocking treatment modalities.