This study attempted to determine whether the Gleason score (GS) assigned at a comprehensive cancer center better predicts risk of biochemical failure (BF) after prostate radiotherapy compared with the GS of the referring institution (RI). Between 1994 and 2007, 1649 men received radiotherapy for prostate cancer at Fox Chase Cancer Center (FCCC). The Cox proportional hazard regression was used for inferences about the relationship of time to BF and GS. Harrell’s C-index (HCI) was used to assess concordance in the Cox regression between predicted and observed events. The discordance rate was 26% for any change in either major or minor Gleason pattern. In the RI GS 2 through 6 group, 79 (8%) patients were upgraded to GS 7. Twenty percent of patients with RI GS 7 were downgraded and 2% were upgraded. In the RI GS 8 through 9 group, 58% were downgraded to GS 6 (12%) or GS 7 (88%). The FCCC GS altered the NCCN risk group assignment in 144 men (9%): 92 (64%) men to lower risk and 52 (36%) to higher risk. FCCC GS was a stronger predictor of BF; the hazard ratios for GS 2 through 6 (ref), 3+4, 4+3, and 8 through 9 were 1.00 (ref), 1.82, 4.14, and 2.92, respectively. In contrast, the hazard ratios for the RI GS were 1.00 (ref), 1.53, 2.44, and 1.76, respectively. FCCC GS (HCI=0.76) had improved performance compared with RI GS (HCI=0.74). Changes in GS were common and the GS assigned by a comprehensive cancer center provided better BF risk stratification and prognostication for patients. Changes in GS may impact treatment recommendations in 9% to 26% of patients.