Porphyromonas gingivalis is a gram-negative anaerobe considered to be a major periodontal pathogen. TLR2 plays a central role in the response to P. gingivalis infection in vivo. In its absence there is a weak inflammatory response; however, bacteria are cleared rapidly compared with wild-type mice. We examined the role of the TLR adaptor proteins MyD88 and TLR/IL-1R-domain-containing adaptor-inducing IFN-beta in the inflammatory response to P. gingivalis in vivo and in the ability to clear the bacterial infection. Proinflammatory cytokine production in response to P. gingivalis infection depends on TLR2, but it does not require MyD88 or TLR/IL-1R-domain-containing adaptor-inducing IFN-beta. In contrast, the generation of intracellular toxic oxygen species and the ultimate clearance of P. gingivalis infection depend critically on MyD88, independent of TLR2. Thus, robust cytokine production and bacterial clearance are independent events mediated by distinct signaling pathways following infection with P. gingivalis.