This study examined the temporal expression of cathepsin D protein and its cellular localization in the spinal cords of rats after a clip compression injury to determine the involvement of cathepsin D in spinal cord injury (SCI). Western blot analysis showed a significant increase in the approximately 31-kDa active form of cathepsin D on days 4 and 7 after the SCI, while the level of the approximately 44-kDa inactive form remained relatively unchanged. Immunohistochemistry revealed cathepsin D with constitutive localization in most neurons and some gliocytes in the normal spinal cord to be intensely immuno-detected primarily in CD68-positive activated macrophages/microglia in the SCI lesions. Overall, these findings suggest that cathepsin D plays an important role in the phagocytosis and lysosomal activation of macrophages/microglia during the central nervous system inflammation caused by trauma.