We compare, in a blinded protocol, five cases of hereditary diffuse leukoencephalopathy with spheroids (HDLS) and ten cases of the pigmentary type of orthochromatic leukodystrophy (POLD), four of which have a family history of neurological illness. Patients presented in the third to sixth decade (mean 41 yrs) with behavioral, cognitive, and motor symptoms. All cases display widespread myelin loss, predominantly fronto-temporal with relative sparing of subcortical U-fibers, and variable numbers of both neuroaxonal spheroids and pigmented glia. Microscopically, spheroids contain amyloid precursor/neurofilament proteins and ubiquitin. Glia and numerous pigmented macrophages stain consistently with diastase-PAS, Sudan black, prolonged Ziehl- Nielsen, and cresyl violet, but variably for iron and ferritin. Ultrastructurally, autofluorescent glial lipopigments consist of lobulated masses of predominantly finely-granular, electron-dense material, consistent with ceroid, an end product of oxidative damage. Glial immunoreactivity to markers of oxidative stress (HO-1, SOD2) and damage (HNE, MAL, NT) is noted, particularly in cases with increased iron and ferritin. These data support the hypothesis that the similar clinico-pathologic features of HDLS and POLD represent a common disease possibly due to an oxidative insult, but further pathogenetic mechanisms should be explored.