Recent studies have suggested that IGF-I and IGF-binding protein (IGFBP)-3, in combination with prostate-specific antigen (PSA), may enhance prostate cancer detection. In this study, we sought to determine the effect on the prediction of future prostate cancer occurrence by incorporating ratios of total and free PSA, IGF-I, IGFBP-3 into PSA testing. Within a population-based prospective cohort study, we investigated the validity (sensitivity and specificity) of plasma concentrations of total and free PSA, IGF-I, and IGFBP-3 and combinations thereof, in 114 cases and 97 controls, in the range of 1.75-13.5 microg/l for PSA, as used by Khosravi et al. (See Ref. 7 ). Validity estimated by the area under the curve in receiver operator characteristics analysis (with 95% confidence interval) for total PSA was 0.78 (range, 0.71-0.84); total/free PSA, 0.69 (range, 0.62-0.76); total PSA/IGF-I, 0.72 (range, 0.65-0.79); free PSA/IGF-I, 0.55 (range, 0.48-0.63); total PSA/IGFBP-3, 0.74 (range, 0.68-0.81); and free PSA/IGFBP-3, 0.57 (range, 0.49-0.64). Analysis of ratios of IGF-I, IGFBP-3, and free and total PSA did not improve validity of PSA testing in the prediction of future occurrence of prostate cancer. It is unlikely that these combinations will improve prostate cancer detection.