Background Identification of markers to aid in understanding the growth kinetics of Von Hippel-Lindau (VHL)-associated clear cell renal cell carcinoma (ccRCC) has the potential to allow individualization of patient care, thereby helping prevent unnecessary screening and optimizing intervention. Purpose To determine whether the degree of restricted diffusion at baseline MRI holds predictive potential for the growth rate of VHL-associated ccRCC. Materials and Methods Patients with VHL disease who underwent surgical resection of tumors between November 2014 and October 2017 were analyzed retrospectively in this HIPAA-compliant study. The change in ccRCC volume between two time points and apparent diffusion coefficient (ADC) at baseline was calculated by using segmentations by two readers at nephrographic-phase CT and diffusion-weighted MRI, respectively. Intraclass correlation coefficient was used to assess agreement between readers. Repeated-measures correlation was used to investigate relationships between ADC (histogram parameters) and tumor size at baseline with growth rate and volume doubling time (VDT). Predictive performance of the ADC parameter with highest correlation and tumor size at baseline was reviewed to differentiate tumors based on their VDT (≤1 year or >1 year). Results Forty-six patients (mean age, 46 years ± 7 [standard deviation]; 25 women) with 100 ccRCCs were evaluated. Interreader agreement resulted in mean κ scores of 0.89, 0.82, and 0.93 for mean ADC, baseline tumor volume, and follow-up tumor volume, respectively. ADC percentiles correlated negatively with tumor growth rate but correlated positively with VDT. Lower ADC values demonstrated stronger correlations. The 25th percentile ADC had the strongest correlation with growth rate (ρ = -0.52, P < .001) and VDT (ρ = 0.60, P < .001) and enabled prediction of VDT (≤1 year or >1 year) with an area under the receiver operating characteristic curve of 0.86 (sensitivity, 67%; specificity, 89%) (P < .001). Conclusion Apparent diffusion coefficient at baseline was negatively correlated with tumor growth rate. Diffusion-weighted MRI may be useful to identify clear cell renal cell carcinomas with higher growth rates. © RSNA, 2020See also the editorial by Goh and Prezzi in this issue.