Purpose: A significant proportion of patients with prostate cancer with Gleason score 6 disease at biopsy is upgraded to Gleason score 7 or higher after radical prostatectomy, increasing the risk of adverse outcome. We identified clinical and pathological parameters that predict pathological upgrading in this population. Materials and Methods: A total of 268 patients with biopsy Gleason score 6 prostate cancer who underwent biopsy and radical prostatectomy between October 1999 and January 2007 were included in the study. Pretreatment characteristics were used to identify predictors of pathological upgrading. Upgrading significance was established by comparing radical prostatectomy pathology between cases that were and were not upgraded. Results: A total of 134 patients (50%) were upgraded postoperatively to Gleason score 7 or higher. Preoperative prostate specific antigen greater than 5.0 ng/ml (p = 0.036), prostate weight 60 gm or less (p = 0.004) and more cancer volume at biopsy, defined by cancer involving greater than 5% of the biopsy tissue (p = 0.002), greater than 1 biopsy core (p <0.001) or greater than 10% of any core (p = 0.014), were associated with pathological upgrading. Upgraded patients were more likely to have extraprostatic extension and positive surgical margins at radical prostatectomy (p <0.001 and 0.001, respectively). Conclusions: Prostate specific antigen, prostate volume and biopsy cancer volume predict clinically significant upgrading in patients diagnosed with Gleason score 6 disease. These parameters may be valuable in the pretreatment risk assessment of this patient population. © 2008 American Urological Association.