The aim of this study was to assess the effect of differences in acquisition technique on whole-brain apparent diffusion coefficient (ADC) histogram parameters, as well as to assess scan-rescan reproducibility. Diffusion-weighted imaging (DWI) was performed in 7 healthy subjects with b-values 0-800, 0-1000, and 0-1500 s/mm(2) and fluid-attenuated inversion recovery (FLAIR) DWI with b-values 0-1000 s/mm(2). All sequences were repeated with and without repositioning. The peak location, peak height, and mean ADC of the ADC histograms and mean ADC of a region of interest (ROI) in the white matter were compared using paired-sample t tests. Scan-rescan reproducibility was assessed using paired-sample t tests, and repeatability coefficients were reported. With increasing maximum b-values, ADC histograms shifted to lower values, with an increase in peak height ( p<0.01). With FLAIR DWI, the ADC histogram shifted to lower values with a significantly higher, narrower peak ( p<0.01), although the ROI mean ADC showed no significant differences. For scan-rescan reproducibility, no significant differences were observed. Different DWI pulse sequences give rise to different ADC histograms. With a given pulse sequence, however, ADC histogram analysis is a robust and reproducible technique. Using FLAIR DWI, the partial-voluming effect of cerebrospinal fluid, and thus its confounding effect on histogram analyses, can be reduced.