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Purpose: We evaluated the usefulness of pre-biopsy multiparametric magnetic resonance imaging and clinical variables to decrease initial prostate biopsies. Materials and Methods: We prospectively evaluated 351 consecutive men with prostate specific antigen between 2.5 and 20 ng/ml, and/or digital rectal examination suspicious for clinically localized disease. All men underwent pre-biopsy multiparametric magnetic resonance imaging and initial 14 to 29-core biopsy, including anterior sampling. Three definitions of significant cancer were defined based on Gleason score and cancer volume (percent positive core and/or maximum cancer length). The overall cohort was divided into men at low risk--prostate specific antigen less than 10 ng/ml and normal digital rectal examination, and high risk--prostate specific antigen 10 ng/ml or greater and/or abnormal digital rectal examination. We evaluated the frequency of significant cancer according to magnetic resonance imaging and risk categories. Clinical variables as significant cancer predictors were analyzed using logistic regression. The sensitivity, specificity, and positive and negative predictive values of magnetic resonance imaging were calculated with or without clinical variables for significant cancer. Results: The frequency of significant cancer in men with negative vs positive magnetic resonance imaging was 9% to 13% vs 43% to 50% in the low risk group and 47% to 51% vs 68% to 71% in the high risk group. In men at low risk with negative magnetic resonance imaging prostate volume was the only significant predictor of significant cancer. In the low risk group the negative predictive value for significant cancer of a combination of positive magnetic resonance imaging and lower prostate volume (less than 33 ml) was 93.7% to 97.5%. Conclusions: Pre-biopsy multiparametric magnetic resonance imaging along with prostate volume decreases the number of initial prostate biopsies by discriminating between significant cancer and other cancer in men with prostate specific antigen less than 10 ng/ml and normal digital rectal examination. [ABSTRACT FROM AUTHOR]