PURPOSE: To determine whether the MR-detectable white matter changes associated with high-dose chemotherapy and bone marrow transplant in patients with advanced breast carcinoma are accompanied by neurochemical disturbances detectable by proton MR spectroscopy. METHODS: MR studies were obtained in 13 patients, and single-voxel proton MR spectra were acquired in vivo in 12 of these 13 for comparison with 13 age- and sex-matched control subjects. RESULTS: Considerable white matter change determined with MR was found in 10 of 13 patients with volume white matter change ranging from 1 to 153 cm3 (mean, 49 cm3; SD, 50 cm3). Single-voxel spectra successfully acquired in 12 patients revealed no significant difference in patients compared with control subjects for the spectral ratios N-acetyl aspartate to creatine or N-acetyl aspartate to choline at either short or long echo times (30 and 136 milliseconds). CONCLUSION: Extensive, late-stage white matter change induced by high-dose chemotherapy is not accompanied by measurable disturbances in the putative neuronal marker N-acetyl aspartate, suggesting that chemotherapy-induced white matter disease is predominantly a water space and possibly an extraneuronal process rather than a primary neuronal (axonal) disease. The MR spectroscopic examination, accomplished at the time of the MR imaging examination, complements the MR imaging study by increasing the specificity of the MR-based clinical evaluation.