Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF-binding proteins (IGFBP) in cancers detected by the prostate-specific antigen (PSA) test. Here, we report the findings of a U.K.-based case-control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50 to 69 years from 2002 to 2009. Participants with an elevated level of PSA (≥3.0 ng/mL) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per SD increase: 1.16; 95% CI: 1.08-1.24; P(trend) < 0.001), IGFBP-2 (1.18; 1.06-1.31; P(trend) < 0.01) and IGFBP-3 (1.27; 1.19-1.36; P(trend) < 0.001), but not IGF-I (0.99; 0.93-1.04; P(trend) = 0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99; 0.91-1.08; P(trend) = 0.62) and IGF-I was inversely associated (0.85; 0.79-0.91; P(trend) < 0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP-2, and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. Although our findings for IGF-I agree with previous results from PSA screening trials, they contrast with positive associations in routinely detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might, nonetheless, prevent its progression.