We assessed whether volume-based complexed prostate-specific antigen (cPSA) indices could enhance prostate cancer detection in men with serum total PSA (tPSA) between 2.5 and 10.0 ng/mL. Between December 1998 and April 2000, cPSA assay was measured in 480 men who underwent transrectal ultrasound-guided prostate biopsies at 7 institutions. We compared the usefulness of cPSA and its indices with the ratio of free PSA (fPSA) to tPSA (percent fPSA) for early detection of prostate cancer. Overall, 168 men (35%) had cancer. In the 341 men with tPSA between 4.01 and 10.0 ng/mL at approximately 90% sensitivity and areas under the receiver operating characteristics curve, the performances of volume-based parameters were significantly better (P <0.05) than those of tPSA and cPSA. In the 139 men with tPSA between 2.5 and 4.0 ng/mL, at 90% sensitivity, the specificity of the ratio of cPSA to tPSA (percent cPSA) was best, followed by cPSA density (cPSAD). In the 101 men with the history of a previous prostate biopsy, at approximately 90% sensitivity, the specificity of cPSAD was significantly better than those of tPSA and percent fPSA (P <0.05). In the 371 men with a total prostate volume of >or=30 cm(3) at approximately 90% sensitivity, the specificity of the cPSAD was significantly better than that of tPSA, percent fPSA, and cPSA (P <0.05). In the 109 men with a total prostate volume of <30 cm(3), at 90% sensitivity the specificity of cPSA and cPSAD was better than that of percent fPSA. In conclusion, volume-based cPSA can modestly enhance the performance of cPSA.