Although multiple sclerosis (MS) lesions have been studied extensively using histology and magnetic resonance imaging (MRI), little is known about diffusely abnormal white matter (DAWM). Diffusely abnormal white matter, regions with reduced mild MRI hyperintensity and ill-defined boundaries, show reduced myelin water fraction, and decreased Luxol fast blue staining of myelin phospholipids, with relative preservation of myelin basic protein and 2′,3′-cyclic-nucleotide 3′-phosphohydrolase. Because DAWM may be important in MS disability and progression, further histologic characterization is warranted. The MRI data were collected on 14 formalin-fixed MS brain samples that were then stained for myelin phospholipids, myelin proteins, astrocytes and axons. Diffusely abnormal white matter showed reduced myelin water fraction (−30%, p < 0.05 for 13 samples). Myelin phospholipids showed the most dramatic and consistent histologic reductions in staining optical density (−29% Luxol fast blue and −24% Weil's, p < 0.05 for 13 and 14 samples, respectively) with lesser myelin protein involvement (−11% myelin-associated glycoprotein, −10% myelin basic protein, −8% myelin-oligodendrocyte glycoprotein, −7% proteolipid protein, −5% 2′,3′-cyclic-nucleotide 3′-phosphohydrolase, p < 0.05 for 3, 3, 1, 2, and 3 samples, respectively). Axonal involvement was intermediate. Diffusely abnormal white matter lipid and protein reductions occurred independently. These findings suggest a primary lipid abnormality in DAWM that exceeds protein loss and is accompanied by axonal degeneration. These phenomena may be important in MS pathogenesis and disease progression, which is prominent in individuals with DAWM.