Dendritic cells are sentinels in innate and adaptive immunity. Upon virus infection, a complex program is in operation, which activates IκB kinase (IKK), a key regulator of inflammatory cytokines and costimulatory molecules. Here we show that the γ₁34.5 protein, a virulence factor of herpes simplex viruses, blocks Toll-like receptor-mediated dendritic cell maturation. While the wild-type virus inhibits the induction of major histocompatibility complex (MHC) class II, CD86, interleukin-6 (IL-6), and IL-12, the γ₁34.5-null mutant does not. Notably, γ₁34.5 works in the absence of any other viral proteins. When expressed in mammalian cells, including dendritic cells, γ₁34.5 associates with IKKα/β and inhibits NF-κB activation. This is mirrored by the inhibition of IKKα/β phosphorylation, p65/RelA phosphorylation, and nuclear translocation in response to lipopolysaccharide or poly(I:C) stimulation. Importantly, γ₁34.5 recruits both IKKα/β and protein phosphatase 1, forming a complex that dephosphorylates two serine residues within the catalytic domains of IκB kinase. The amino-terminal domain of γ₁34.5 interacts with IKKα/β, whereas the carboxyl-terminal domain binds to protein phosphatase 1. Deletions or mutations in either domain abolish the activity of γ₁34.5. These results suggest that the control of IκB kinase dephosphorylation by γ₁34.5 represents a critical viral mechanism to disrupt dendritic cell functions.