OBJECTIVE. The purpose of this prospective study was to assess the clinical utility of generalized autocalibrating partial parallel acquisition (GRAPPA)-accelerated readout-segmented echo-planar imaging (rs-EPI) DWI and compare it with standard single-shot EPI (-ss-EPI) DWI in visualization of the prostate during 3-T MRI. SUBJECTS AND METHODS. One hundred sixteen consecutively registered patients (mean age, 63.5 years; range 24-93 years) underwent 3-T MRI that included rs-EPI DWI and standard ss-EPI DWI with identical FOVs, slices, acceleration factors, b values, and image postprocessing procedure. The datasets were independently evaluated by two blinded radiologists. Images were evaluated for sharpness, anatomic distortion, imaging contrast, lesion conspicuity, detailed anatomic visualization, and overall image quality on a 5-point Likert scale (1, nondiagnostic; 5, excellent). RESULTS. The kappa values were 0.73 for image sharpness, 0.71 for anatomic distortion, 0.54 for imaging contrast, 0.56 for lesion conspicuity, 0.61 for detailed anatomic visualization, and 0.63 for overall image quality (all p < 0.05), indicating moderate to substantial agreement between the two observers. The mean Likert scores for standard ss-EPI and -rs-EPI were as follows: image sharpness, 2.9 and 4.6; distortion level, 2.8 and 4.4; contrast, 3.1 and 3.8; lesion conspicuity, 3.0 and 4.0; structure, 3.1 and 4.2; and overall image quality, 3.1 and 4.2. The rs-EPI DWI sequence was associated with significantly better image quality and fewer susceptibility artifacts than was ss-EPI (all p < 0.05). The rs-EPI sequence was considered better overall in 90% of cases. CONCLUSION. The technique of rs-EPI DWI combined with GRAPPA enables robust prostate imaging with high image quality and may provide great benefit in routine clinical practice.