Although quantitative magnetic resonance (MR) studies have shown that primary progressive multiple sclerosis (PPMS) patients have subtle and diffuse changes of the normal-appearing brain tissue (NABT), the nature of these changes is still poorly understood. The aim of this study was to improve our understanding of the NABT damage in PPMS patients by comparing diffusion tensor magnetic resonance (DT MR) quantities of a large portion of the brain from these patients with those from healthy subjects with and without T2-visible lesions. Dual-echo and DT MR images of the brain were obtained from 20 patients with PPMS, 20 age- and gender-matched healthy volunteers with normal conventional MR scans of the brain, and 20 age-, gender- and T2 lesion volume-matched healthy subjects. Mean diffusivity (MD) and fractional anisotropy (FA) histograms of the NABT were derived from all the individuals. Average lesion MD and FA were calculated in PPMS patients and healthy controls with T2-visible lesions. MD and FA histogram-derived metrics of the NABT from PPMS patients differed significantly from the corresponding quantities from healthy volunteers with no brain T2-visible lesions and from those from healthy volunteers with overt brain MR abnormalities (p values ranging from < 0.0001 to 0.01). Average lesion MD was also significantly higher in PPMS patients than in healthy volunteers with T2-visible lesions (p = 0.03). In PPMS patients, no significant correlation was found between any of the DT MR quantities of NABT damage and a) the T2 lesion volume, b) the average lesion MD, and c) the normalized brain volume. This study shows that in PPMS patients there is a significant microscopic damage of the NABT which is independent of the extent of T2-visible abnormalities. This suggests that Wallerian degeneration of fibers passing through macroscopic abnormalities is not a major factor contributing to diffuse NABT pathology of these patients.