The purpose of this study was the immunocytochemical mapping of proteins PTHrP, PTHR1 and MSX1 within the cellular population of central (CGCG) and peripheral (PGCG) giant cell granulomas and the comparison of their expression between the two groups of lesions. Material and Methods This study included biopsy material from 20 lesions which were diagnosed as CGCG and 20 lesions which were diagnosed as PGCG. The material was retrieved from the Department of Oral Pathology and Medicine, Dental School, National and Kapodistrian University of Athens, and the Division of Oral Pathology, Department of Diagnostic Sciences, Dental School, University of Minnesota, USA. The following antibodies were used, a) polyclonal rabbit anti-PTHrP, b) polyclonal rabbit anti-PTHR1and mouse monoclonal ant-MSX1. The results were blindly evaluated and each specimen and each antibody were assessed regarding the percentage of stained multinucleated giant cells type I and type II and oval and spindle-shaped mononuclear cells. Results PTHrP and PTHR1 were expressed by nearly all multinucleated giant cells type I and oval mononuclear cells both in CGCG and PGCG specimens. In all CGCG and PGCG specimen nearly all giant cells type I strongly expressed MSX1 within the cytoplasm and around the nuclear membrane. A strong nuclear MSX1 expression was also observed by almost all oval and spindle-shaped mononuclear cells in most CGCG and PGCG specimen. Conclusions The PTHrP, PTHR1 and MSX1 proteins are variably expressed by CGCG and PGCG cell populations. The presence of PTHrP and PTHR1 in both CGCG and PGCG substrate cells indicates the possible formation of osteoclast giant cells through the typical osteoclastogenetic process, whereas the expression of those molecules by the multinuclear giant cells indicates the possible presence of an independent autocrine/paracrine process of osteoclastogenesis. Since no difference in the expression of PTHrP and PTHR1 between CGCG and PGCG lesions was observed despite the different clinical behaviour of the two lesions, the formation of the giant cells through the PTHrP-PTHR1 mechanism does not seem to have any obvious effect on the clinical and biological behaviour of the lesions. The strong MSX1 expression by mononuclear cells suggests the intense cell multiplication and supports their osteoblastic origin and differentiation. The CGCG association with residual dental follicle cells through MSX1, may explain the almost exclusive development of CGCG within the dentigerous areas of the jaws and its increased prevalence lesion in patients around the age of tooth formation.