BACKGROUND. To enhance the specificity of PSA in diagnosis of cancer, several approaches have been evaluated, having in common the study of fractions of PSA. The aim of this study was to evaluate the usefulness of complexed PSA in the differential diagnosis between benign prostate hyperplasia (BPH) and prostate cancer. METHODS. We determined the concentrations of complexed PSA (Bayer, Tarrytown, NY) and total PSA (Tandem-R Assay, Hybritech Incorporated, San Diego, CA) in 196 patients with BPH and in 55 patients with prostate cancer. Likewise, the percentage of free PSA (Wallac, Turku, Finland) was determined for 124 of these patients. RESULTS. The specificity of complexed PSA was found to be greater than that of total PSA for the cutoff values corresponding to sensitivities of 80%, 85%, and 90%. Similarly, the area under the curve obtained by receiver-operating curve analysis was greater for complexed PSA than for total PSA, although significant differences were not observed. The diagnostic usefulness of complexed PSA in the differential diagnosis between BPH and prostate cancer was found to be lower than the percentage of free PSA. CONCLUSIONS. We believe that differential diagnosis with complexed PSA between BPH and prostate cancer is of little use, due to low efficacy when PSA results are extreme.