Tissue injury, such as burns or inflammation, can lead to the generation of oxidized lipids capable of regulating hemodynamic, pulmonary, immune, and neuronal responses. However, it is not known whether traumatic injury leads to a selective upregulation of transcripts encoding oxidative enzymes capable of generating these mediators. Here, we analyzed microarrays taken from circulating leukocytes of 187 trauma subjects compared with 97 control volunteers for changes in the expression of 105 oxidative enzymes and related receptors. The results indicate that major blunt trauma triggers a selective change in gene expression, with some transcripts undergoing highly significant upregulation (e.g., CYP2C19), while others display significantly reduced expression (e.g., CYP2U1). This pattern in gene expression was maintained for up to 28 days after injury. In addition, the level of expression of CYP2A7, CYP2B7P1, CYP2C19, CYP2E1, CYP4A11, CYP4F3, CYP8B1, CYP19A1, CYP20A1, CYP51A1, HMOX2, NCF1, NCF2, and NOX1 and the receptors PTGER2 and ESR2 were correlated with clinical trauma indices such as APACHE II, Max Denver Scale, and the Injury Severity Score. Demonstration of a selective alteration in expression of transcripts encoding oxidative enzymes reveals a complex molecular response to major blunt trauma in circulating leukocytes. Furthermore, the association between changes in gene expression and clinical trauma scores suggests an important role in integrating pathophysiologic responses to blunt force trauma.