Abstract Activation of the Akt pathway plays a pivotal role in regulating the inflammatory response. Rictor is a component of the mTORC2 complex, and its loss has been shown to abrogate the phosphorylation of Akt at serine 473. However, the biological importance of mTORC2 in innate immunity is currently unknown. Here we demonstrate that rictor plays a critical role in TLR-signaling via its ability to regulate FoxO1. Genetic deletion or siRNA-mediated knockdown of rictor enhanced the production of pro-inflammatory cytokines upon LPS-stimulation, whereas the levels of the anti-inflammatory cytokine IL-10 were suppressed. The hyper-inflammatory phenotype was due to a defective Akt signaling axis, since rictor-deficient cells or rictor knockdown DC exhibited attenuated Akt phosphorylation and kinase activity, whereas complementation with a constitutively active Akt ablated the enhanced inflammatory response. Analysis of downstream targets showed phosphorylation of FoxO1 was impaired in rictor-deficient or rictor knockdown cells. The loss of rictor resulted in elevated levels of nuclear FoxO1 and an inability to export FoxO1 into the cytoplasm upon TLR-stimulation, an event that was restored upon complementation with a constitutively active Akt. FoxO1 deletion in DC resulted in an attenuated TLR mediated inflammatory response in which rictor knockdown was unable to rescue. These findings identify a novel signaling pathway by which mTORC2 regulates the TLR-mediated inflammatory response