Obesity is associated with increased risk of positive surgical margins and prostate specific antigen (PSA) recurrence among men undergoing radical prostatectomy. To what degree positive margins contribute to poorer outcome is unclear. Thus, we sought to examine the association between body mass index (BMI) and more objective measures of tumor aggressiveness, tumor grade and size. We carried out a retrospective analysis of 2302 patients treated with radical prostatectomy at the Duke Prostate Center from 1988-2007. Tumor volume was calculated by multiplying prostate weight by percent of specimen involved with cancer. Associations between BMI and tumor volume and high-grade disease (Gleason >or=4+3) independent of pre-operative clinical characteristics of age, race, PSA, clinical stage, biopsy Gleason sum, and year of surgery were assessed using linear and logistic regression, respectively. Mean and median BMI among all subjects was 28.1 and 27.6 kg m(-2), respectively. Increased BMI was significantly associated with younger age (P<0.001), black race (P<0.001), more recent year of surgery (P<0.001), and positive surgical margins (P<0.001). After adjusting for multiple clinical pre-operative characteristics, higher BMI was associated with a greater percent of the prostate involved with cancer (P=0.003), increased tumor volume (P<0.001), and high-grade disease (P=0.007). Men with a BMI >or=35 kg m(2) had nearly 40% larger mean tumor volumes than normal weight men (5.1 versus 3.7 cc), after adjustment for multiple clinical characteristics. In this study, obese men undergoing radical prostatectomy had higher-grade and larger tumors, providing further evidence that obese men undergoing radical prostatectomy have more aggressive prostate cancers.