Histone deacetylases (HDACs), which remove acetyl groups from lysine residues of histone and non-histone proteins, are key molecular mediators of inflammation. However, their roles in anti-microbial host defence are less well understood. We previously reported that the class IIa HDAC, HDAC7, is expressed at elevated levels in inflammatory macrophages. Here we investigated the role of HDAC7 in macrophage anti-microbial responses. Transgenic mice that selectively over-express HDAC7 in the myeloid compartment (mac-HDAC7 mice) were generated, and macrophages from these mice were assessed for their phagocytic potential and capacity to clear intracellular bacteria. Mac-HDAC7 macrophages displayed increased phagocytosis of heat-killed E. coli as compared to control cells, an effect that correlated with elevated expression of specific phagocytic receptors. These macrophages also generated increased levels of reactive oxygen species upon infection with E. coli, and were more effective than control cells at clearing intracellular E. coli at acute time-points. Conversely, treatment of wild type primary murine macrophages with TMP269, a class IIa HDAC inhibitor, impaired phagocytosis and intracellular bacterial clearance. Myeloid-specific deletion of HDAC7 also led to impaired phagocytosis and intracellular bacterial clearance, further confirming a non-redundant role for this HDAC in host defence. Collectively, our data suggest that class IIa HDACs are important components of innate defence against bacterial infection, acting at the level of both gene regulation and acute signalling during phagocytic responses. Current studies are focused on identifying molecular targets of HDAC7 linked to acute regulation of immediate reactive oxygen species production. These findings provide key insights into our understanding of macrophage anti-microbial pathways and have important implications for the development of selective HDAC inhibitors as anti-inflammatory agents.