The aim of this study was to compare the diagnostic utility of complexed prostate-specific antigen (cPSA) with total PSA (tPSA) in screening for prostate cancer. Serum concentrations of tPSA and cPSA were measured in 4479 adult men during the prostate cancer screening program in the Saarland region (Germany). The percentage of men with c/tPSA ratio above the cut-off value of 0.75 increased with increasing tPSA intervals: tPSA 0–0.9 µg/l, 4.4%; 1.0–1.9 µg/l, 24.3%; 2.0–2.9 µg/l, 43.9%; 3.0–3.9 µg/l, 50.4%; and 4.0–20 µg/l, 60.2%. The commonly accepted tPSA cut-off value of 3.9 µg/l matched to the 93rd percentile of the overall population (corresponding cPSA value, 2.9 µg/l). A total of 202 men out of 313 with increased cPSA had increased c/tPSA ratio (cut-off ≥ 0.75) vs. 186 out of 312 men with increased tPSA. Thus, an additional 16 men at high risk for prostate cancer were selected only if cPSA was utilised as a first line parameter. Our data show that, compared to tPSA, cPSA measurement will always detect more high-risk patients, independent of the cut-off levels utilised for cPSA, tPSA and c/tPSA ratio. cPSA is more effective than tPSA in selecting subjects with an elevated c/tPSA ratio who are at high risk of prostate cancer. Thus, cPSA might be seen as the superior first-line parameter in screening for prostate cancer. Using lower cut-off values for tPSA or cPSA than the commonly accepted values seems reasonable for screening purposes.