Fifteen multiple sclerosis patients were examined by diffusion tensor imaging (DTI) to determine fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in a superventricular volume of interest of 8 x 8 x 2 cm(3) containing gray matter (GM) and white matter (WM) tissue. Point resolved spectroscopy 2D-chemical shift imaging of the same volume was performed without water suppression. The water contents and DTI parameters in 64 voxels of 2 cm(3) were compared. The water content was increased in patients compared with controls (GM: 244+/-21 vs. 194+/-10 a.u.; WM: 245+/-32 vs. 190+/-11 a.u.), FA decreased (GM: 0.226+/-0.038 vs. 0.270+/-0.020; WM: 0.337+/-0.044 vs. 0.402+/-0.011) and ADC increased [GM: 1134+/-203 vs. 899+/-28 (x10(-6) mm(2)/s); WM: 901+/-138 vs. 751+/-17 (x10(-6) mm(2)/s)]. Correlations of water content with FA and ADC in WM were strong (r=-0.68, P<0.02; r=0.75; P<0.01, respectively); those in GM were weaker (r=-0.50, P<0.05; r=0.45, P<0.1, respectively). Likewise, FA and ADC were more strongly correlated in WM (r=-0.88; P<0.00001) than in GM (r=-0.69, P<0.01). The demonstrated relationship between DTI parameters and water content in multiple sclerosis patients suggests a potential for therapy monitoring in normal-appearing brain tissue.