Purpose: To compare readout-segmented echo-planar imaging (EPI) (RESOLVE) to single-shot EPI (ss-EPI) diffusion-weighted imaging (DWI) for the assessment of renal interstitial fibrosis. Materials and Methods: A phantom, eight healthy volunteers (under 30 years to avoid age-fibrosis related) and 27 chronic kidney disease (CKD) patients (scheduled for kidney biopsy) were scanned (at 3T) with ss-EPI and 5-shot RESOLVE DWI (resolution: 2 x 2 x 5mm(3), 10 b-values). The cortico-medullary difference for each DW parameter from a monoexponential fit (ADC) or, segmented biexponential fit (D, D*, F-p) were compared between both sequences. A fibrosis threshold of 40% was defined to separate all 35 subjects into low and high fibrosis groups. The linear relationship between DW parameters and percentage fibrosis (up to 80%) from Masson trichrome was assessed with the Pearson product-moment correlation coefficient. Fisher Z-transform was used for R-2 correlation comparison. Results: A coefficient of variation between ADCs of 3% was measured between both sequences in the phantom. In healthy volunteers, no significant difference was measured for all DW parameters. Both sequences separated low to high level of fibrosis with a significant decrease of ADC (RESOLVE P=3.1 x 10(-6), ss-EPI P=0.003) and D (RESOLVE P=8.2 x 10(-5), ss-EPI P=0.02) in the high level of fibrosis. However, RESOLVE ADC had a stronger negative correlation (P=0.04 for R-2 comparison) with fibrosis than ss-EPI ADC (RESOLVE R-2=0.65, P=5.9 x 10(-9), ss-EPI R-2=0.29, P=8.9 x 10(-4)). D (RESOLVE) was correlated (moderately) with fibrosis (R-2=0.29, P=9.2 x 10(-4)); however, D* and F-p did not show, in our population, a significant correlation with interstitial fibrosis (0.01 < R-2 < 0.08). Conclusion: ADC derived from both sequences correlated with fibrosis. ADC from RESOLVE showed better correlation with fibrosis than ADC from ss-EPI and therefore has potential to monitor CKD.