Purpose: To prospectively investigate whether T1 changes in normal-appearing white matter (WM) and normal-appearing gray matter (GM) in multiple sclerosis (MS) are global or regional and their relationship to disease type. Materials and Methods: The institutional ethics review board approved study; written informed consent was obtained. Whole-brain T1 maps were obtained in 67 patients with MS and 24 healthy control subjects with three-dimensional fast low-angle shot flip angle-array method, with correction for B1 imperfections. Analysis of variance was performed on T1 histogram parameters of global normal-appearing WM and GM. Regional mean T1 values were analyzed with a multilevel approach. Multiple linear regression analysis was performed to investigate associations with clinical disability and overall atrophy. For patients, T2 lesion load was determined. Results: T1 histograms of normal-appearing WM had significantly higher peak positions for patients with MS (792 msec ± 36 in secondary progressive [SP] MS) than for control subjects (746 msec ± 23) and were significantly broader and lower (all P < .001). Histograms for cortical normal-appearing GM were significantly shifted (peak positions, 1263 msec ± 44 in control subjects and 1355 msec ± 62 in patients with SP MS) (P < .001). Histogram peak positions were significantly higher in SP MS than in relapsing-remitting (RR) and primary progressive MS (P < .05). In SP disease, at least 31% of normal-appearing WM and 20% of cortical normal-appearing GM were affected. In MS, T1 was significantly elevated in all normal-appearing WM and cortical normal-appearing GM regions (all P < .01) but was elevated only in the thalamus in deep GM (P < .05). Cortical T1 histogram peak position was associated with clinical disability; T2 lesion load was not. Conclusion: Results suggest that a global disease process affects large parts of both normal-appearing WM and GM in MS and effects are worse for SP MS than for RR MS.