© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Background: Interleukin-1 and Porphyromonas gingivalis both signal through the IL-1R/TLR superfamily but have distinct effects on osteoclastogenesis. Results: IL-1 and P. gingivalis lipopolysaccharide (LPS-PG) differentially regulate osteoclast genes and osteoclastogenic transcription factor NFATc1, as well as transcription repressor Blimp1 and anti-osteoclastogenic genes. Conclusion: Multiple signaling molecules are involved in distinct IL-1R/TLR2-mediated effects on osteoclastogenesis. Significance: This is a novel mechanism for understanding infection/inflammation-mediated osteoclastogenesis.