Epigenetic regulation of gene expression could help explain variation in responses to infection and differences in disease susceptibility in cattle. The aim of this study was to examine epigenetic mechanisms in the regulation of LPS-induced innate immune gene expression in peripheral blood mononuclear cells (PBMCs) from five healthy calves. Firstly, epigenetic enzyme gene expression (histone deacetylase (HDAC) and DNA methyltransferase (DNMT)) was measured after LPS stimulation. Secondly, the effect of the histone deacetylase inhibitor Trichostatin A (TSA) on histone H3 acetylation and on innate immune gene expression was also measured. Results showed differential expression of HDAC6, HDAC7 and DNMT3A genes in response to LPS in cells from all animals, while TSA significantly inhibited pro-inflammatory cytokine (TNF, IL2 and IFNG) expression (P<), presumably by histone acetylation. These results suggest an important role for the HDAC family of enzymes in the regulation of bovine innate immune gene expression.