Mutations of the copper-zinc superoxide dismutase (SOD1) gene can result in the development of amyotrophic lateral sclerosis (ALS). The exact cellular mechanisms causing ALS are not known, but oxidative stress is thought to play a prominent role. Lysyl oxidase (LOX) is one of the genes that are known to be up-regulated in ALS patients. In this study, we examined LOX localization in wild type rat and mouse brain sections using immunohistochemistry coupled with laser-scanning confocal microscope. The results showed that LOX, an extracellular matrix protein, was expressed in the choroid plexus, blood vessel walls, brain matrix, and neurons of normal rat and mice. In neurons, LOX was localized within the cytoplasm. LOX immunoreactivity increased in neurons of the spinal cord, brain stem and cortex, and the Purkinje cells of the cerebellum in transgenic G93A SOD1 (mSOD1) mouse model of ALS. In situ hybridization indicated that LOX gene expression was enhanced in the neurons of the spinal cord, brain stem, cortex, caudoputamen and cerebellum in mSOD1 mice compared with wild type controls. LOX enzyme activity was increased in mSOD1 mice. An increase in the amount of LOX mRNA, protein and enzyme activity was coincidental with late stage ALS, indicating that LOX may be associated with the progression of the neurodegenerative process in the mSOD1 model of ALS.