Purpose To test the impact of existing Prostate Imaging Reporting and Data System (PI-RADS) version 2 (V2) decision rules, as well as of proposed adjustments to these decision rules, on detection of Gleason score (GS) 7 or greater (GS ≥7) prostate cancer. Materials and Methods Two radiologists independently provided PI-RADS V2 scores for the dominant lesion on 343 prostate magnetic resonance (MR) examinations. Diagnostic performance for GS ≥7 tumor was assessed by using MR imaging-ultrasonography fusion-targeted biopsy as the reference. The impact of existing PI-RADS V2 decision rules, as well as a series of exploratory proposed adjustments, on the frequency of GS ≥7 tumor detection, was evaluated. Results A total of 210 lesions were benign, 43 were GS 6, and 90 were GS ≥7. Lesions were GS ≥7 in 0%-4.1% of PI-RADS categories 1 and 2, 11.4%-27.1% of PI-RADS category 3, 44.4%-49.3% of PI-RADS category 4, and 72.1%-73.7% of PI-RADS category 5 lesions. PI-RADS category 4 or greater had sensitivity of 78.9%-87.8% and specificity of 75.5%-79.1 for detecting GS ≥7 tumor. The frequency of GS ≥7 tumor for existing PI-RADS V2 decision rules was 30.0%-33.3% in peripheral zone (PZ) lesions upgraded from category 3 to 4 based on dynamic contrast enhancement (DCE) score of positive; 50.0%-66.7% in transition zone (TZ) lesions upgraded from category 3 to 4 based on diffusion-weighted imaging (DWI) score of 5; and 71.7%-72.7% of lesions in both zones upgraded from category 4 to 5 based on size of 15 mm or greater. The frequency of GS ≥7 tumor for proposed adjustments to the decision rules was 30.0%-60.0% for TZ lesions upgraded from category 3 to 4 based on DWI score of 4; 33.3%-57.1% for TZ lesions upgraded from category 3 to 4 based on DCE score of positive when incorporating new criteria (unencapsulated sheetlike enhancement) for DCE score of positive in TZ; and 56.4%-61.9% for lesions in both zones upgraded from category 4 to 5 based on size of 10-14 mm. Other proposed adjustments yielded GS ≥7 tumor in less than 15% of cases for one or more readers. Conclusion Existing PI-RADS V2 decision rules exhibited reasonable performance in detecting GS ≥7 tumor. Several proposed adjustments to the criteria (in TZ, upgrading category 3 to 4 based on DWI score of 4 or modified DCE score of positive; in PZ or TZ, upgrading category 4 to 5 based on size of 10-14 mm) may also have value for this purpose. © RSNA, 2016 Online supplemental material is available for this article.