Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by neuronal loss and gliosis mainly in specific subcortical nuclei, but also in the cerebral cortex. In addition to neuron loss, hyperphosphorylated tau deposition is found in neurons, astrocytes and coiled bodies. Limited studies have shown that certain oxidative products are increased in the PSP brain. The present study examines oxidative damage in the frontal cortex in 7 PSP compared with 8 age-matched controls. Western blotting of the frontal cortex showed increased 4-hydroxy-2-nonenal (HNE)-immunoreactive bands between 40 and 50 kDa in PSP cases. Bi-dimensional gel electrophoresis and Western blotting, together with mass spectometry, were used to identify HNE-modified proteins. Oxidized phosphoglycerate kinase 1 (PGK-1) and fructose bisphosphate aldolase A (aldolase A) were identified in all cases and 4 of 7 PSP cases, respectively. In contrast, PGK-1 and aldolase A were oxidized in 3 of 8 controls. Immunohistochemistry revealed the localization of aldolase A in neurons and astrocytes, and PGK-1 mainly in astrocytes. These findings show that PGK-1 and aldolase A are targets of oxidation in the frontal cortex in the aged human cerebral cortex and that oxidative damage of these proteins is markedly increased in the frontal cortex in PSP.