OBJECTIVE Parathyroid hormone-related peptide (PTHrP) binds to the parathyroid hormone receptor type 1 (PTHR1), which results in the activation of pathways in osteoblasts that promote osteoclastogenesis through the RANK/RANKL system. RANK/RANKL expression has been shown in central giant cell granuloma of the jaws but PTHrP/PTHR1 has not. MSX1 protein is a classical transcription regulator which promotes cell proliferation and inhibits cell differentiation by inhibiting master genes in tissues such as bone and muscle. It has been implicated in the pathogenesis of cherubism, and its expression has been reported in a single central giant cell granuloma (CGCG) case. We aimed, therefore, to study the expression of those proteins by the different cellular populations of central and peripheral giant cell granulomas (PGCGs) of the jaws. METHODS Twenty cases of CGCG and 20 cases of PGCG of the jaws were retrospectively examined by immunohistochemistry for the percentage of positively staining cells to antibodies for PTHrP, PTHR1, and MSX1, using a semiquantitative method. RESULTS In both CGCG and PGCG of the jaws, PTHrP and PTHR1 were abundantly expressed by type I multinucleated giant cells (MGC) and mononucleated stromal cells (MSC) with vesicular nuclei, whereas type II MGC and MSC with pyknotic nuclei expressed those proteins to a lesser extent. In both CGCG and PGCG of the jaws, MSX1 was abundantly expressed by type I MGC and MSC but type II MGC did not express it. A statistically significant difference (P < .05) was observed between CGCG and PGCG in the expression of PTHrP in type II MGC and MSC with pyknotic nuclei and in the expression of PTHR1 in type II MGC. CONCLUSIONS We suggest that in CGCG and PGCG of the jaws, PTHrP-positive immature osteoblasts activate PTHR1-positive mature osteoblasts to produce RANKL which interacts with RANK on the PTHrP/PTHR1-positive osteoclast-precursor cells found in abundance in the stroma of giant cell lesions and induces osteoclastogenesis through the classic pathway. Cells of the jawbones, the periodontal ligament, or the dental follicle, originating from the neural crest, may be involved in the pathogenesis of giant cell lesions of the jaws. Further study is required for these suggestions to be proved.