BACKGROUND: Pseudorabies virus (PRV) is an alphaherpesviruses whose native host is pig. PRV infection mainly causes signs of central nervous system disorder in young pigs, and respiratory system diseases in the adult. RESULTS: In this report, we have analyzed native host (piglets) gene expression changes in response to acute pseudorabies virus infection of the brain and lung using a printed human oligonucleotide gene set from Illumina. A total of 210 and 1130 out of 23,000 transcript probes displayed differential expression respectively in the brain and lung in piglets after PRV infection (p-value < 0.01), with most genes displaying up-regulation. Biological process and pathways analysis showed that most of the up-regulated genes are involved in cell differentiation, neurodegenerative disorders, the nervous system and immune responses in the infected brain whereas apoptosis, cell cycle control, and the mTOR signaling pathway genes were prevalent in the infected lung. Additionally, a number of differentially expressed genes were found to map in or close to quantitative trait loci for resistance/susceptibility to pseudorabies virus in piglets. CONCLUSION: This is the first comprehensive analysis of the global transcriptional response of the native host to acute alphaherpesvirus infection. The differentially regulated genes reported here are likely to be of interest for the further study and understanding of host viral gene interactions.