High-resolution diffusion tensor imaging (DTI) was performed in 14 patients with clinically definite multiple sclerosis (MS) and the trace of the diffusion tensor (<D>) and the fractional anisotropy (FA) were determined in normal appearing white matter (NAWM) and in different types of focal MS lesions. A small but significant increase of the <D> in NAWM compared to control white matter ((840 +/- 85) x 10(-6) mm(2)/sec vs. (812 +/- 59) x 10(-6) mm(2)/sec; P < 0.01) was found. In addition, there was a significant decrease in the FA of normal-appearing regions containing well-defined white matter tracts, such as the genu of the internal capsule. In non-acute lesions, the <D> of T(1)-hypointense areas was significantly higher than that of T(1)-isointense lesions ((1198 +/- 248) x 10(-6) mm(2)/sec vs. (1006 +/- 142) x 10(-6) mm(2)/sec; P < 0. 001), and there was a corresponding inverse relation of FA. Diffusion characteristics of active lesions with different enhancement patterns were also significantly different. DTI with a phase navigated interleaved echo planar imaging technique may be used to detect abnormalities of isotropic and anisotropic diffusion in the NAWM and selected fiber tracts of patients with MS throughout the entire brain, and it demonstrates substantial differences between various types of focal lesions.