The aim of this study was to compare gene expression profiles of leukocytes from blood (WBCs) and spleen harvested at an early time point after injury or sham injury in mice subjected to trauma/hemorrhage, burn injury or lipopolysaccharide (LPS)-infusion at three experimental sites. Groups of injured or LPS-infused animals and sham controls were sacrificed at two hours following injury and resuscitation, blood and spleen were harvested and leukocyte populations recovered after erythrocyte lysis. RNA was extracted from post-lysis leukocyte populations. Complementary RNA was synthesized from each RNA sample and hybridized to microarrays. A large number (500-1400) of genes were differentially expressed at the two hour time point in injured or LPS-infused versus sham animals. Thirteen of the differentially expressed genes in blood, and 46 in the spleen, were upregulated or downregulated in common among all three animal models and may represent a common, early transcriptional response to systemic inflammation from a variety of causes. The majority of these genes could be assigned to pathways involved in the immune response and cell death. The up or down regulation of a cohort of 23 of these genes was validated by RT-PCR. This large-scale microarray analysis shows that at the two hour time point there is marked alteration in leukocyte gene expression in three animal models of injury and inflammation. While there is some commonality among the models, the majority of the differentially expressed genes appear to be uniquely associated with the type of injury and/or the inflammatory stimulus.