Abstract: Recent data from our laboratory have shown a regionally specific increase in lipid peroxidation in postmortem progressive supranuclear palsy (PSP) brain. To extend this finding, we measured activities of mitochondrial enzymes as well as tissue malondialdehyde (MDA) levels in postmortem superior frontal cortex (Brodmann’s area 9; SFC) from 14 pathologically confirmed cases of PSP and 13 age‐matched control brains. Significant decreases (‐39%) in α‐ketoglutarate dehydrogenase complex/glutamate dehydrogenase ratio and significant increases (+36%) in tissue MDA levels were observed in the SFC in PSP; no differences in complex I or complex IV activities were detected. Together, these results suggest that mitochondrial dysfunction and lipid peroxidation may underlie the frontal metabolic and functional deficits observed in PSP.