Immune activation in multiple trauma is closely linked to the development of multiple organ dysfunction and failure, and consequently, has a profound influence on patient outcome. Although peripheral blood monocytes play a critical role in this immune response, the biological significance of changes in genome-wide expression immediately after traumatic injury have not been explored previously. Thirteen patients presenting with multiple blunt trauma were studied. Peripheral blood monocytes were obtained within 90 min and at 6, 12, 24, 48, and 72 h after trauma. Apparent genome-wide expression was determined with Affymetrix U133A microarrays. Supervised analysis identified 698 probe sets that were differentially expressed in the 13 trauma subjects (P < 0.001) over the 72-h study period. An additional 763 probe sets were differentially expressed in patients who died (n = 3) compared with those who survived (n = 10). The ability of these probe sets to function as a classifier of survival was significantly demonstrated with six prediction models. Using pathway analysis, a network of proinflammatory genes and intracellular signaling pathways leading to c-JUN activation were consistently overexpressed in patients who died. Genome-wide mRNA expression patterns in circulating peripheral blood monocytes from multiple-injured patients can discriminate clinical outcome. The pattern of gene expression in patients who died suggests that in these individuals, there is a reprioritization of gene expression consistent with an early activation of selected genes involved in the initiation and propagation of a proinflammatory response.