Whereas it is important to gain prognostic information in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS), there is still a lack of definitive data about the significance of normal-appearing white (NAWM) and gray (NAGM) matter damage in these patients. The aim of this study was to clarify the role of magnetization transfer magnetic resonance imaging (MT MRI) in assessing "occult" damage at the earliest clinical stage of MS. Dual echo, post-contrast T1-weighted, and MT MRI were obtained from 43 CIS patients with paraclinical evidence of spatial disease dissemination within 3 months from disease onset and from 22 controls. In patients, conventional MRI was obtained after 3 and 12 months from the baseline assessment, to detect disease dissemination in time (DIT). A neurological examination was also conducted to ascertain the occurrence of relapses for an average follow up period of 1389 (range = 420-1847) days. MTR maps were derived and NAWM and NAGM MT ratio (MTR) histograms were analyzed. During the follow up, 30 patients showed MRI evidence of DIT, and 21 experienced a relapse. T2 lesion volume (LV) was significantly higher in patients with DIT than in those without (p=0.005). MTR histogram variables did not significantly differ between patients with MRI or clinical DIT. T2 LV was the only significant predictor of clinical DIT at follow-up (p=0.001). This study shows that MT MRI-detectable damage to NAWM and NAGM may not be an important feature of all patients at presentation with a CIS highly suggestive of MS and that such a damage may develop with subsequent disease evolution.