Circulating insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) levels have been associated with common diseases. Although family-based studies suggest that genetic variation contributes to circulating IGF-I and IGFBP-3 levels, analyses of associations with multiple IGF-I and IGFBP-3 single nucleotide polymorphisms (SNP) have been limited, especially among African Americans. We evaluated 30 IGF-I and 15 IGFBP-3 SNPs and estimated diplotypes in association with plasma IGF-I and IGFBP-3 among 984 premenopausal African American and Caucasian women. In both races, IGFBP-3 rs2854746 (Ala³²Gly) was positively associated with plasma IGFBP-3 (CC versus GG mean difference among Caucasians, 631 ng/mL; 95% confidence interval, 398-864; African Americans, 897 ng/mL; 95% confidence interval, 656-1,138), and IGFBP-3 diplotypes with the rs2854746 GG genotype had lower mean IGFBP-3 levels than reference diplotypes with the CG genotype, whereas IGFBP-3 diplotypes with the CC genotype had higher mean IGFBP-3 levels. IGFBP-3 rs2854744 (-202 A/C) was in strong linkage disequilibrium with rs2854746 in Caucasians only, but was associated with plasma IGFBP-3 in both races. Eight additional IGFBP-3 SNPs were associated with ≥5% differences in mean IGFBP-3 levels, with generally consistent associations between races. Twelve IGF-I SNPs were associated with ≥10% differences in mean IGF-I levels, but associations were generally discordant between races. Diplotype associations with plasma IGF-I did not parallel IGF-I SNP associations. Our study supports that common IGFBP-3 SNPs, especially rs2854746, influence plasma IGFBP-3 levels among African Americans and Caucasians but provides less evidence that IGF-I SNPs affect plasma IGF-I levels. (Cancer Epidemiol Biomarkers Prev 2009;18(3):954–66)