Serial monthly magnetization transfer (MT) imaging was performed to evaluate whether a change of the normal appearing white matter (NAWM), which precedes the appearance of enhancing lesions, is seen in patients with multiple sclerosis (MS). Every 4 weeks for 3 months, 10 patients with relapsing-remitting MS were scanned with a T1-weighted sequence, 20 minutes after injection with 0.3 mmol/kg gadolinium-DTPA (Gd-DTPA). During each of the monthly sessions, MT and dual echo scans were also performed before Gd-DTPA injection. On coregistered images, the MT ratio (MTR) was measured in NAWM subsequently involved by enhancing lesions, in NAWM areas on the same slices but outside any present or future MR abnormality, and in enhancing lesions at the time of their appearance. Forty-eight new enhancing lesions with no corresponding abnormalities on previous scans were identified. Their average MTR was 33.1% (+/-8.4%). Three, 2, and 1 month before enhancement appearance, the mean MTR in NAWM, measured from areas corresponding to future enhancing lesions, was significantly lower than the mean MTR in NAWM outside enhancing areas; the MTR decreased steadily as the time when the enhanced lesion approached. These results suggest that changes in the NAWM of patients with MS occur before lesions become evident on conventional MRI scans.