The role of the insulin-like growth factor (IGF) axis and whether IGFs interact with androgen-suppressing agents in relation to prostate carcinogenesis is unclear. This nested case-control study (n = 1,652 cases/1,543 controls) examined whether serum IGF1, IGF2, IGFBP2, IGFBP3, and the IGF1:IGFBP3 ratio were associated with prostate cancer in the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Baseline serum was assayed for IGF-axis analytes using ELISA. Logistic regression estimated ORs and 95% confidence intervals for risk of total, low-grade (Gleason 2-6) and high-grade (Gleason 7-10) cancers. Results were stratified by intervention assignment. In both the placebo and finasteride arms, serum IGF1, IGF2, IGFBP3, and the IGF1:IGFBP3 ratio were not associated with prostate cancer. However, men in the highest versus lowest quartile of serum IGFBP2 had a 48% (P(trend) = 0.02) and 55% (P(trend) = 0.01) increased risk for total and low-grade cancers, respectively. These IGFBP2 associations were attenuated and no longer statistically significant in the finasteride arm. Our results suggest that in general, serum IGF-axis analytes were not associated with prostate cancer risk in the PCPT in which presence or absence of all cancers was biopsy-determined. The exception was the finding that high serum IGFBP2 is a risk factor for low-grade disease, which was attenuated for men on finasteride. Further research is needed to understand better the risk incurred by high IGFBP2 and whether androgen-suppressing agents such as finasteride influence aspects of IGFBP2 physiology relevant to prostate carcinogenesis.