Autopsy specimens are often used in molecular biological studies of disease pathophysiology. However, few analyses have focused specifically on postmortem changes in skeletal muscles, and almost all of those investigate protein or metabolic changes. While some structural and enzymatic changes have been described, the sequence of transcriptional events associated with these remains unclear. We analyzed a series of new and pre-existing human skeletal muscle datasets on 12,500 genes and ESTs generated by the Affymetrix U95Av2 GeneChips from seven autopsy and seven surgical specimens. Remarkably, postmortem specimens (up to 46 hours) revealed a significant and prominent up-regulation of transcripts involved with protein biosynthesis. Additional up-regulated transcripts are associated with cellular responses to oxidative stress, hypoxia and ischemia, however, only a subset of genes in these pathways was affected. Over-expression was also seen for apoptosis, cell cycle regulation/arrest and signal transduction related genes. No major gene expression differences were seen between autopsy specimens with <20 hour and 34-46 hour-postmortem intervals or between pediatric and adult cases. These data demonstrate that, likely in response to hypoxia and oxidative stress, skeletal muscle undergoes a highly active transcriptional, and possibly, translational phase during the initial 46 hour postmortem interval. Knowledge of these changes is important for proper interpretation of gene expression studies utilizing autopsy specimens.