The insulin-like growth factor (IGF) axis plays a role in growth and progression of prostate cancer. High circulating IGF-1 levels have been associated with an increased risk of prostate cancer. Results for IGF binding protein 3 (IGFBP-3) are inconclusive. Some studies have indicated that the positive association with IGF-1 is observed only for low-grade prostate cancer (Gleason sum < 7). We previously reported in the Health Professionals Follow-up Study (HPFS) a direct positive association between ELISA-measured plasma IGF-1 and IGFBP-3 and risk of prostate cancer (462 cases diagnosed after providing a blood specimen (between 1993 and 1995), but before February 1998). With additional follow-up through January 31st 2004, and 1,331 case-control pairs in total, we were now able to investigate low-grade (Gleason sum < 7, n = 635) and high-grade (Gleason sum ≥ 7, n = 515) prostate cancer separately. Matched odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. ORs of total prostate cancer comparing top to bottom quartiles were 1.41 (95% CI 1.12-1.78, p-trend = 0.001) for IGF-1 and 1.58 (95% CI 1.24-2.01, p-trend = 0.003) for IGFBP-3. IGF-1 was more strongly associated with low-grade (OR = 1.61 top versus bottom quartile, 95% CI 1.16-2.25, p-trend = 0.01), than with high-grade (OR = 1.29, 95% CI 0.89-1.88, p-trend = 0.12) prostate cancer (p-heterogeneity = 0.08). We hypothesize that these findings reflect that high-grade prostate cancers are more autonomous, and, thus, less sensitive to the action of IGF-1 than low-grade cancers.