Damage to the cerebral cortex results in neurological impairments such as motor, attention, memory and executive dysfunctions. To examine the molecular mechanisms contributing to these deficits, mRNA expression was profiled using high-density cDNA microarray hybridization after experimental cortical impact injury in mice. The mRNA levels at 2 h, 6 h, 24 h, 3 days and 14 days after injury were compared with those of control animals. This revealed 86 annotated genes and 24 expression sequence tags (ESTs) as being differentially expressed with a 1.5-fold or greater change. Quantitative real-time PCR analysis was used to independently verify these results for selected genes. Seven functional classes of genes were found to be altered following injury, including transcription factors, signal transduction genes and inflammatory proteins. While a few of these genes have been previously reported to be differentially regulated following injury, the most of the genes have not been previously implicated in traumatic brain injury (TBI) pathophysiology. For example, consistent with previous reports, the transcription factor c-jun and the neurotrophic factor bdnf mRNA levels were altered as a result of TBI. Among the novel genes, the mRNA levels for the high mobility group protein 1 (hmg-1), the regulator of G-protein signaling 2 (rgs-2), the transforming growth factor beta inducible early growth response (tieg), the inhibitor of DNA binding 3 (id3), and the heterogeneous nuclear ribonucleoprotein H (hnrnp h) were changed following injury. The functional significance of these genes in neurite outgrowth, neuronal regeneration, and plasticity following injury are discussed.