Q-space analysis is an alternative analysis technique for diffusion-weighted imaging (DWI) data in which the probability density function (PDF) for molecular diffusion is estimated without the need to assume a Gaussian shape. Although used in the human brain, q-space DWI has not yet been applied to study the human spinal cord in vivo. Here we demonstrate the feasibility of performing q-space imaging in the cervical spinal cord of eight healthy volunteers and four patients with multiple sclerosis. The PDF was computed and water displacement and zerodisplacement probability maps were calculated from the width and height of the PDF, respectively. In the dorsal column white matter, q-space contrasts showed a significant (P < 0.01) increase in the width and a decrease in the height of the PDF in lesions, the result of increased diffusion. These q-space contrasts, which are sensitive to the slow diffusion component, exhibited improved detection of abnormal diffusion compared to perpendicular apparent diffusion constant measurements. In white matter (WM) the axonal membrane and myelin sheath present barriers to water displacement, resulting in anisotropic diffusion (1-4). WM damage is known to affect tissue microstructure and diffusion-weighted MRI (DWI) has been used to measure changes in diffusion properties (both parallel and perpendicular to WM fiber bundles) in a number of WM diseases in humans (5) as well as animal models of myelin deficiency (6,7). In general, however, conclusive assignment of diffusion changes observed with DWI to axonal and/or myelin damage is not straightforward, in part because the biophysics of diffusion in vivo is not fully understood and because axonal and myelin loss are histopathologically related. Additionally, the technique selected to analyze diffusion-weighted images (DWIs) is an important consideration and has an impact on the quantitative interpretation of diffusion experiments. DWIs are typically analyzed with a monoexponential tensor model that characterizes the observed signal decay according to the Stejskal-Tanner equation (8):where S/S 0 is the normalized signal intensity, ␥ is the proton gyromagnetic ratio, ␦, G, and ⌬ are the duration, magnitude, and leading edge separation time of the diffusion weighting gradient vector, respectively, and D is the diffusion tensor. Diffusion tensor imaging (DTI) has been applied in the brain (5,9 -12) and spinal cord (10,(13)(14)(15) and is typically performed in the low b-value (Ͻ1500 s/mm 2 ) regime where the signal decay is, to a reasonable approximation, monoexponential. The degree to which diffusion is reduced in the CNS, compared to free water, is the result of microstructural barriers, which generally includes multiple compartments in vivo and the diffusion time that molecules have to explore their environment. If restrictions between compartments are sufficiently large so that exchange is slow on the MR timescale, the signal attenuation will become non-monoexponential. This effect becomes apparent at higher b-values (Ͼ1500 s/mm 2 )...