The aim of this study was to investigate the potential prognostic value of preoperative serum prostate-specific antigen levels adjusted for total tumor volume (PSA-TTV density) for outcome following radical prostatectomy for prostate cancer by retrospective review in 268 patients. Lower PSA-TTV density was not only associated with a significantly higher risk for biological failure (bF), systemic failure and cancer death but also an independent predictor for bF (hazard ratio, 6.3). Therefore, these data suggest that there are subsets of prostate cancer with lower PSA secretion levels, and this phenotype is associated with a higher risk of failure after surgery.