This study was conducted to assess if sonographic discrimination between healthy and cancerous prostate tissue might be improved using regional analysis of ultrasound (US) Doppler measures. A total of 39 subjects underwent 3-D Doppler sonography before radical prostatectomy. Cancer locations were identified from hematoxylin and eosin (H&E)-stained slides. Three prostate data volumes consisting of a frequency shift and power-mode Doppler US and whole mount histology images were spatially registered for each prostate, then divided into entirely 1 mL-sized regions of cancerous or noncancerous tissue. Each prostate was visually divided into a peripheral and a periurethral region within which US Doppler measures were calculated. Receiver operating characteristic (ROC) and simulated biopsy analyses within each prostate were performed. Mean speed in colored pixels (V), and speed-weighted pixel density (SWD) are good discriminators for prostate cancer in the periurethral and the peripheral regions, respectively. Using SWD in a simulated biopsy yields increased cancer detection in the peripheral region.