We examined the effects of spinal cord injury (SCI) on alterations in gene expression and respective protein products in human skeletal muscle 2 and 5d post-SCI. Biopsies were taken from skeletal muscle of 9 men and 1 woman (N=10) (43.9 + 6.7 years) 2 and 5d post-SCI and from 5 healthy young men who served as controls (20.4 + 0.5 years). Global changes in gene expression were analyzed using Affymetrix GeneChips on a subsample of subjects (N=3). Candidate genes were then pursued via qRT-PCR. Western blotting (WB) was used to quantify protein products of candidate genes. Immunohistochemistry (IHC) was used to localize proteins. Groups of transcripts showing the greatest percentage of altered expression, the most robust fold-changes, and indicative of involvement of an entire pathway using the GeneChip included genes involved in the ubiquitin proteasome pathway (UPP), metallothionein function, and protease inhibition. qRT-PCR analysis confirmed increases in gene expression for UPP components (UBE3C, Atrogin-1, MuRF, and PSMD11), the metallothioneins (MT1A, MT1F, MT1H), and the protease inhibitor, SLPI, (p<0.05) at 2 and 5d post-SCI. Protein levels of the proteasome subunit (PSMD11) and the metallothioneins were increased 5d post-SCI. Protein levels of UBE3C, Atrogin-1, MuRF and SLPI were unchanged (p>0.05). IHC showed increased staining for PSMD11 and the metallothioneins 5d post-SCI, along the peripheral region of the cells. IHC also showed altered staining for Atrogin-1 at 5d post-SCI along the membrane region. Thus, there was a profound increase in gene expression of UPP components, the metallothioneins, and the protease inhibitor, SLPI, within 5d of SCI. Increased protein levels for PSMD11 and the metallothioneins 5d post-SCI, specifically along the cell periphery, indicate that proteins in this region may be early targets for degradation post-SCI.