Objectives: No consensus exists regarding the prognostic value of tumor volume (TV) in predicting biochemical recurrence (BCR) of prostate cancer, especially late in the prostate-specific antigen (PSA) era. We assessed this relationship in a large cohort of patients treated at one institution with standardized pathologic assessment from 1998 to 2005. Methods: Data were collected for 1833 patients undergoing radical prostatectomy for clinically localized prostate cancer since 1998. Patients receiving neoadjuvant or adjuvant therapy or with node-positive disease were excluded. Along with the routine pathologic assessment, TV was prospectively assessed in all specimens. BCR was defined as two consecutive PSA levels of 0.2 ng/mL or one PSA level of greater than 0.2 ng/mL. Results: Although a larger TV correlated with lower rates of biochemical relapse-free survival in patients with a surgical Gleason score of 7 (P <0.0001) and surgical Gleason score of 8 or greater (P = 0.0459), the biochemical relapse-free survival rate at 4 years for low, medium, and extensive surgical Gleason score 6 or less tumors was 95%, 96%, and 97%, respectively (P = 0.65). In a multivariate model, including TV, initial PSA, EPE, seminal vesicle invasion, and surgical Gleason score, the TV predicted for BCR (P = 0.0176). Conclusions: The results of this large study suggest that a large TV is an independent predictor of BCR in patients with tumors of specimen Gleason score 7 or higher. In contrast, most grade 6 tumors will be organ confined, even if of high volume, and TV will not predict for BCR in these patients. © 2007 Elsevier Inc. All rights reserved.