ZBTB46 and DC-SCRIPT/ZNF366 are two zinc finger transcription factors that play important roles in regulating differentiation of dendritic cells in mammals. In this study, the ZBTB46 and DC-SCRIPT/ZNF366 homologues were identified in rainbow trout Oncorhynchus mykiss and their expression analysed in vivo and in vitro. As transcription factors, they are well conserved in sequence, genomic organisation and gene synteny. Their expression was differentially modulated by bacterial and viral PAMPs in the monocyte/macrophage-like cell line RTS-11, in primary head kidney (HK) macrophages, and in HK macrophages cultured with IL-4/13A. In the RTS-11 cells and primary HK macrophages, all the ZBTB46 and DC-SCRIPT/ZNF366 homologues were down-regulated by interferon gamma (type II IFN) but unaffected by IFN2 (type I IFN), administered as recombinant proteins to cell cultures. In fish gills, infection with amoebae (Paramoebae perurans) resulted in reduction of ZBTB46 and DC-SCRIPT/ZNF366 expression in Atlantic salmon Salmo salar, whilst infection with Yersinia ruckeri induced gene expression in rainbow trout.