OBJECTIVE We compare the ability of several prostate specific antigen (PSA) parameters, including PSA density of the whole prostate and of the transition zone, percent free PSA and PSA velocity, to enhance the specificity for prostate cancer detection and to reduce unnecessary biopsies in men with serum PSA levels of 4 to 10.0 ng./ml. METHODS This prospective study included 559 consecutive men referred for early prostate detection or lower urinary tract symptoms who had a serum PSA of 4.0 to 10.0 ng./ml. All men underwent prostatic ultrasonography and sextant biopsy with 2 additional transition zone biopsies. Specific biopsies of abnormal findings on digital rectal examination were also performed. In all cases if first biopsies were negative an additional set of biopsies was performed within 6 weeks. The ability of PSA density, PSA transition zone, PSA velocity and percent free PSA to improve the power of PSA in the detection of prostate cancer was evaluated with univariate and multivariate analyses as well as receiver operating characteristics (ROC) curves. RESULTS Of 559 patients 342 had histologically confirmed benign prostatic hyperplasia and 217 had prostate cancer. Mean serum PSA, PSA velocity, PSA density and PSA transition zone were statistically higher (p <0.018, p <0.037, p <0.0001 and p <0.0001, respectively) and percent free PSA was statistically lower (p <0.0001) in patients with prostate cancer than in those with benign disease. Multivariate analysis and ROC curves showed that PSA transition zone and percent free PSA were the most powerful and highly significant predictors of prostate cancer. Areas under the ROC curve for PSA transition zone and percent free PSA were 0.827 and 0.778, respectively (p=0.01 McNemar test). Combination of free-to-total PSA with PSA transition zone significantly increased the area under the ROC curve compared to PSA transition zone alone (p=0.020). With a 95% sensitivity for prostate cancer detection a PSA transition zone cutoff of 0.25 ng./ml./cc would result in the lowest number of unnecessary biopsies (47% PSA transition zone specificity) compared to all other PSA parameters. However, total prostate volume (greater than 30 cc in 422 men or less than 30 cc in 137) was an important factor in predicting the statistical performance of PSA transition zone. In fact, PSA transition zone did not outperform free percent PSA in sensitivity and specificity when the entire prostate gland volume was less than 30 cc (p=0.094 McNemar test). CONCLUSIONS PSA density of the transition zone enhances the specificity of serum PSA for prostate cancer detection in referred patients with a serum PSA of 4.0 to 10.0 ng./ml. compared to other PSA parameters currently available. While PSA transition zone was more effective in prostates greater than 30 cc and percent free PSA was more effective in prostates less than 30 cc, the combination of percent free PSA with PSA transition zone further increased prostate cancer prediction.