OBJECTIVE In contemporary screening populations a major drawback of prostate specific antigen (PSA) is its relative lack of specificity, especially in the range of 4 to 10 ng/ml, where prostate cancer is found 25% of the time. ProPSA is a derivative of free PSA (fPSA) consisting of the truncated forms (eg [-2]proPSA, [-4]proPSA or the full-length [-7]proPSA). There is increasing evidence that proPSA is associated preferentially with prostate cancer. The objective of this study was to determine whether proPSA can influence the detection of early prostate cancer. METHODS Archival serum samples obtained from 93 men who underwent a systematic 12-core prostate biopsy (total PSA range 4.0 to 10.0 ng/ml) were assayed for percent free PSA, total PSA and the 3 forms of proPSA (Hybritech Tandem Assays Beckman Coulter Access, Beckman Coulter, Inc., Brea, California). Free PSA, the cumulative sum of individual proPSA forms ([-2], [-4] and [-7], or sum-proPSA) and derivatives were determined. Of the 93 men assessed 41 (44%) had evidence of prostate cancer (76% Gleason 5/6, 19% Gleason 7 and 5% Gleason 8). Prostate volume was measured at systematic 12-core biopsy for the detection of prostate cancer. Results were analyzed using univariate and multivariate logistic regression (LR) nonparametric statistical methods. RESULTS Using univariate LR, fPSA, percent fPSA (%fPSA), percent sum-proPSA and prostate volume significantly (p <0.05) differentiated men with prostate cancer from those with benign disease. However, applying stepwise backward multivariate LR, total PSA, %fPSA and sum-proPSA were retained and generated a receiver operator characteristic curve with an area under the curve of 76.6%. At 90% sensitivity these 3 variables collectively achieved a specificity of 44% for the detection of prostate cancer. Individually, the 3 retained variables had a specificity of 23% (total PSA), 33% (%fPSA) and 13% (sum-proPSA). CONCLUSIONS Sum-proPSA, total PSA and %fPSA in combination improve the specificity of early prostate cancer detection in men with a total PSA of 4 to 10 ng/ml compared with the results of individual PSA molecular forms measured.