The aim of the present study is to investigate age-related changes in water self-diffusion in cerebral white matter by analysing diffusion-weighted MRI from a sample of 54 healthy volunteers. A voxel-based analysis of the relative anisotropy and the apparent diffusion coefficients was performed by applying an optimized normalization protocol. Linear regression analysis revealed significant correlations with age in the corpus callosum, prefrontal regions, the internal capsule, the hippocampal complex, and the putamen. However, in other regions, such as those surrounding the ventricles, the insula, or the inferior frontal plane, significant correlations between age and ADC were observed, presumably as a result of morphological age-related variations. A mask procedure was carried out in order to distinguish between morphological involvement and real age-related white matter changes. Our results indicate that in interpreting the changes in each significant region it is necessary to proceed with precaution because the voxel-based statistical analysis might yield a mixture of two effects: (i) morphological changes that remain after the normalization procedure and (ii) actual diffusivity parameter changes. Anatomically defined regions of interest may help us to minimize morphologic involvement and draw comparisons with findings previously published.