Radiologists and scientists who interpret and study prostate MRI.Restriction Spectrum Imaging (RSI) is a multiple b-value, multidirectional advanced diffusion weighted imaging (DWI) technique which aims to minimize signal derived from the extracellular hindered as well as the cylindrically restricted pools of water molecules and focus contribution from the isotropic, intracellular, truly restricted pool (1). This has been used to advantage in Neuroimaging, producing greater accuracy than conventional imaging measures in differentiating areas of glioblastoma multiforme infiltrative tumor involvement from normal appearing cerebral white matter (2). We have demonstrated that this provides greater quantitative discrimination of prostate cancer from normal prostate compared to conventional multiparametric MRI (MP-MRI) parameters in a prior study. In this study, we evaluated for overall clinical utility of this technique, specifically assessing reader performance of RSI in isolation and in combination with MP-MRI.Three readers independently evaluated 100 patients (67 with proven PCa) who underwent MP-MRI and RSI within six months of biopsy or prostatectomy. Readers used a five-point scale estimating the likelihood of PCa present in each prostate sextant. Evaluation was performed in two separate sessions, first using conventional MP-MRI alone then immediately with MP-MRI and RSI in the same session. Four weeks later, another scoring session used RSI and T2 without conventional diffusion-weighted or dynamic contrast-enhanced imaging. Reader interpretations were then compared to prostatectomy data or biopsy results. Receiver operating characteristic (ROC) curves were performed, with area under the curve (AUC) used to compare across groups. MP-MRI with RSI achieved higher AUCs compared to MP-MRI alone for identifying high grade PCa (0.78 versus 0.70 at the sextant level; P <0.001 and 0.85 versus 0.79 at the hemigland level; P = 0.04). RSI and T2 alone achieved AUCs similar to MP-MRI for high grade PCa (0.71 versus 0.70 at the sextant level). With hemigland analysis, high grade disease results were similar when comparing RSI+T2 with MP-MRI although with greater AUCs (0.80 versus 0.79).Including RSI with MP-MRI improves PCa detection compared to MP-MRI alone, and RSI with T2 achieves similar PCa detection as MP-MRI.MP-MRI, including DCE and conventional DWI, serves as the current standard of care after many years of effort to improve the detection and localization of PCa via imaging. Many studies support the added benefit of DCE and, particularly, DWI to standard anatomic T1 and T2 sequences (3,4). However, DCE requires intravenous contrast administration, resulting in the burden of longer scan time, patient discomfort, and the risk of adverse reaction. Conventional DWI is compromised by severe spatial distortion, limiting its ability to be coregistered to anatomic images, which is necessary for tumor localization. Additionally, conventional DWI fails to exclude signal from the extracellular hindered and cylindrically restricted water pools, decreasing tumor conspicuity thought to be possible with advanced DWI techniques such as RSI (1). Additional improvements in methodology are the subject of considerable ongoing research efforts. RSI has shown promise in prior quantitative based studies, and this data supports true clinical utility as demonstrating improved performance via RSI in a reader-based format, as reflects the current practice model at most centers. This suggests RSI may serve as a valuable addition to current standard of care imaging, or possibly as a viable surrogate imaging measure in those unable to undergo comprehensive MP-MRI.