Purpose:To determine the interpatient variability of prostate peripheral zone (PZ) apparent diffusion coefficient (ADC) and its effect on the assessment of prostate cancer aggressiveness.Materials and Methods:The requirement for institutional review board approval was waived. Intra- and interpatient variation of PZ ADCs was determined by means of repeated measurements of normal ADCs at three magnetic resonance (MR) examinations in a retrospective cohort of 10 consecutive patients who had high prostate-specific antigen levels and negative findings at transrectal ultrasonographically-guided biopsy. In these patients, no signs of PZ cancer were found at all three MR imaging sessions. The effect of interpatient variation on the assessment of prostate cancer aggressiveness was examined in a second retrospective cohort of 51 patients with PZ prostate cancer. Whole-mount step-section pathologic evaluation served as reference standard for placement of regions of interest on tumors and normal PZ. Repeated-measures analysis of variance was used to determine the significance of the interpatient variations in ADCs. Linear logistic regression was used to assess whether incorporating normal PZ ADCs improves the prediction of cancer aggressiveness.Results:Analysis of variance revealed that interpatient variability (1.2-2.0 A-A?A 1/2 10(-3) mm(2)/sec) was significantly larger than measurement variability (0.068 A-A?A 1/2 10(-3) mm(2)/sec A-A?A 1/2 0.027 [standard deviation]) (P = .0058). Stand-alone tumor ADCs showed an area under the receiver operating characteristic curve (AUC) of 0.91 for discriminating low-grade versus high-grade tumors. Incorporating normal PZ ADC significantly improved the AUC to 0.96 (P = .0401).Conclusion:PZ ADCs show significant interpatient variation, which has a substantial effect on the prediction of prostate cancer aggressiveness. Correcting this effect results in a significant increase in diagnostic accuracy.A-A?A 1/2 RSNA, 2012.