Currently, transrectal ultrasound (TRUS) guided biopsy is the only method for definitive diagnosis of prostate cancer. Our current study used a high-frequency (i.e., 29-MHz), transrectal, micro-ultrasound system (ExactVu™ micro-ultrasound, Exact Imaging) to acquire RF data from 163 patients immediately before needle firing during 12-core biopsy examinations. Quantitative ultrasound (QUS) estimates of effective scatter diameter (ESD), effective acoustic concentration (EAC), midband (M), intercept (I), and slope (S) were calculated. Additional QUS estimates were derived including envelope statistics employing a Nakagami distribution and the envelope signal-to-noise ratio (ESNR). Estimate values were used to train linear-discriminant classifiers and performance was assessed using area-under-the-curve (AUC) values obtained from receiver operating characteristic (ROC) analyses based on 10-fold cross validation. A combination of ESS- and EAC-related parameters produced an AUC value of 0.75. When ESNR or PSA value was added as a feature, the AUC increased significantly to 0.77 or 0.78, respectively. The best classifier performance was obtained by combining envelope statistics, PSA, ESD, and EAC, which produced an AUC of 0.80. Our initial results with AUC values of 0.80 are very encouraging for developing a new tool for prostate-cancer biopsy guidance and treatment.