OBJECTIVE: To determine if magnetic resonance imaging (MRI)/ultrasound fusion-targeted prostate biopsy (TB) would lead to increased recommendations of aggressive radiotherapy treatments for higher risk prostate cancer compared to systematic biopsy (SB) results. METHODS: Clinicopathologic data of 533 men who underwent both TB and SB from 2014 to 2017 was analyzed. TB was performed in addition to SB in patients with detection of MRI suspicious lesions. Three patient cohorts were established: (1) biopsy naïve (80/533, 15.0%), (2) active surveillance (185/533, 34.7%), and (3) prior negative biopsy (268/533, 50.3%). Cancer risk categorical criteria were established with recommended radiotherapy treatment for each. Variation of risk classification due to biopsy method for all patients and within each cohort was analyzed using either a chi-squared statistic or Fisher's exact test. McNemar's pairwise analyses were performed for all risk categories between TB and SB to assess the effects of TB on high-risk cancer identification and subsequent radiotherapy recommendations. RESULTS: Number of patients within cancer risk categories (1. "No Cancer or Low-Risk"; 2. "More Favorable Intermediate-Risk"; 3. "Less Favorable Intermediate-Risk"; 4. "High-Risk") varied significantly based on TB and SB pathology among all patients combined (P <.0001), in cohort 2 (P = .0005), and in cohort 3 (P <0.0001). Further, among all patients, TB increased cancer risk classification and correspondingly would result in more aggressive radiotherapy recommendations: "No Cancer or Low-Risk" to "Less Favorable Intermediate-Risk" (30/343, P <0.0001) and "No Cancer or Low-Risk" to "High-Risk" (31/353, P <.0001). CONCLUSION: Among men with prostate cancer, TB commonly led to reclassification to a higher risk group, which is accompanied by more aggressive radiotherapy treatment recommendations when compared with SB findings alone.