Biomarkers based on diffusion-weighted imaging (DWI) have been proposed as potential disease biomarkers in several brain conditions including cerebral small vessel disease (SVD). Often histogram-based metrics are extracted, but findings across studies are somehow inconsistent. Here, we investigated the impact of several processing options for extracting histogram metrics of fractional anisotropy (FA) and mean diffusivity (MD) from DWI. We considered two white matter regions-of-interest with different interpolation and thresholding options, as well as different numbers of bins. We found that processing options significantly impacted histogram metrics, which in some cases significantly affects the ability to discriminate between patient and controls.