Abstract Objectives: Periodontal disease (PD) is a polymicrobial inflammatory lesion in which pathogenic bone loss is caused by osteoclasts (OC) differentiated from MCSF/RANKL-primed monocytes. Elevated IgG antibody to a keystone opportunistic pathogen, Porphyromonas gingivalis (Pg), is a hallmark humoral response in PD that is correlated with pathogenic bone loss. Whereas, a cell membrane protein, osteoclast stimulatory transmembrane protein (OC-STAMP), is engaged in cell-fusion event required for OC-genesis. This study examined the humoral immune responses to OC-STAMP expressed by human monocytes in relation to anti-Pg antibody. Methods: Blood serum (N=10) collected from systemically healthy human subjects (Precision for Medicine) were measured for IgG antibody titer to Pgor OC-STAMP peptides. Human peripheral blood mononuclear cells were stimulated with MCSF/RANKL with or without anti-OC-STAMP rabbit polyclonal antibody or control rabbit IgG. Affinity purified human anti-OC-STAMP antibody was also tested for its activity to alter the OC-genesis. OC-genesis induced in vitrowas evaluated by TRAP staining and pit formation assay. Results: IgG antibody titer to Pgpositively correlated with that to human OC-STAMP peptides (r=0.579, p<0.05). Anti-OC-STAMP auto-antibody purified from human serum with high IgG antibody titer to Pg, as well as anti-OC-STAMP rabbit antibody significantly promoted in vitroOC-genesis (p<0.05). Conclusions: The results indicated that Pginfection may be associated with development of anti-OC-STAMP auto-antibody which can promote OC-genesis, suggesting a novel immunological intervention in the pathogenesis of PD. Supported by grants from NIH NIDCR grants, DE-027851, DE-028715 and DE-331851