Complex signaling pathways regulate the innate immune system of insects, with NF-?B transcription factors playing a central role in the activation of antimicrobial peptides and other immune genes. Although numerous studies have characterized the immune responses of insects to pathogens, comparatively little is known about the counterstrategies pathogens have evolved to circumvent host defenses. Among the most potent immunosuppressive pathogens of insects are polydnaviruses that are symbiotically associated with parasitoid wasps. Here, we report that the Microplitis demolitor bracovirus encodes a family of genes with homology to inhibitor ?B (I?B) proteins from insects and mammals. Functional analysis of two of these genes, H4 and N5, were conducted in Drosophila S2 cells. Recombinant H4 and N5 greatly reduced the expression of drosomycin and attacin reporter constructs, which are under NF-?B regulation through the Toll and Imd pathways. Coimmunoprecipitation experiments indicated that H4 and N5 bound to the Rel proteins Dif and Relish, and N5 also weakly bound to Dorsal. H4 and N5 also inhibited binding of Dif and Relish to ?B sites in the promoters of the drosomycin and cecropin All genes. Collectively, these results indicate that H4 and N5 function as I?Bs and, circumstantially, suggest that other I?B-like gene family members are involved in the suppression of the insect immune system. Microplitis demolitor (Braconidae) Parasites diseases and disorders; Diseases and disorders; Microbial diseases; Immunology and repair mechanisms Microplitis demolitor; Viral diseases; Inhibitor ?B-like proteins; role in immune response suppression; Microplitis demolitor bracovirus; Immune like reactions; Immune response supression none