In spite of marked disability, patients with primary progressive multiple sclerosis (PPMS) display smaller lesion volumes on conventional magnetic resonance imaging (MRI) compared with other forms of multiple sclerosis (MS). Hence, damage to the normal-appearing brain tissue (NABT) may play an important role in explaining the pathogenesis of disability in PPMS. Diffusion-weighted MRI (DW-MRI) probes water diffusion in vivo that can be altered by pathologic changes. Using DW-MRI we investigated diffusion in the NABT of 15 patients with PPMS over one year. The average apparent diffusion coefficient (ADC_av) was measured in 10 regions of interest located in the normal-appearing thalamus and the normal-appearing white matter (NAWM). Six healthy subjects served as a reference. In contrast to healthy subjects, patients with PPMS showed an increment within 12 months of the ADC_av in NAWM which was associated with an increase of the T2- and T1-lesion volumes. The ADC_av in frontal NAWM was associated with disability as measured by the MS Functional Composite Measure. Serial DW-MRI depicts progressive changes in the NAWM of patients with PPMS. Our preliminary findings suggest that the processes causing structural damage in NAWM and lesions in patients with PPMS are partially linked and that changes of water diffusion in NAWM depicted by DW-MRI are clinically relevant.