Porphyromonas gingivalis, a major etiologic agent of periodontitis, has been reported to induce the expansion of myeloid-derived suppressor cells (MDSC); however, little is known regarding the subpopulations of MDSC expanded by P. gingivalis infection. Flow cytometry was used to evaluate bone marrow and spleen cells from mice infected with P. gingivalis and controls for surface expression of CD11b, Ly6G, and Ly6C. To characterize the phenotype of MDSC subpopulations induced by infection, cells were sorted based on the differential expression of Ly6G and Ly6C. Moreover, since MDSC are suppressors of T cell immune activity, we determined the effect of the induced subpopulations of MDSC on the proliferative response of OVAspecific CD4+ T cells. Lastly, the plasticity of MDSC to differentiate into osteoclasts was assessed by staining for tartrate-resistant acid phosphatase activity. P. gingivalis infection induced the expansion of three subpopulations of MDSC (Ly6G++ Ly6C+, Ly6G+ Ly6C++, and Ly6G+ Ly6C+); however, only CD11b+ Ly6G+ Ly6C++-exp ressing cells exerted a significant suppressive effect on T cell proliferation. Inhibition of proliferative responses required T cell-MDSC contact and was mediated by inducible nitric oxide synthase and cationic amino acid transporter 2 via gamma interferon. Furthermore, only the CD11b+ Ly6G+ Ly6C++ subpopulation of MDSC induced by P. gingivalis infection was able to differentiate into osteoclasts. Thus, the inflammatory response induced by P. gingivalis infection promotes the expansion of immune-suppressive cells and consequently the development of regulatory inhibitors that curtail the host response. Moreover, monocytic MDSC have the plasticity to differentiate into OC, thus perhaps contributing to the OC pool in states of periodontal disease.