Genetic factors influence circulating insulin-like growth factor-one (IGF-I) and IGF binding protein-3 (IGFBP-3) levels. Prior studies with multiple IGF-I and IGFBP-3 polymorphisms have been limited, especially among African Americans. We evaluated 30 IGF-I and 15 IGFBP-3 single nucleotide polymorphisms (SNPs) and estimated diplotypes in relation to plasma levels of both proteins among 984 premenopausal African Americans and Caucasians from the National Institute of Environmental Health Sciences Uterine Fibroid Study. In both racial groups, IGFBP-3 rs2854746 (Ala32Gly) was associated with plasma IGFBP-3, (CC versus GG: Caucasians: 631 ng/ml, 95% confidence interval (CI): 398, 864; African Americans: 897 ng/ml, 95% CI: 656, 1138). Relative to diplotypes with the rs2854746 CG genotype, IGFBP-3 diplotypes with the GG genotype had lower mean plasma IGFBP-3 while IGFBP-3 diplotypes with the CC genotype had higher mean plasma IGFBP-3. The IGFBP-3 promoter SNP, rs2854744, which was in strong linkage disequilibrium with rs2854746 in Caucasians only, was associated with plasma IGFBP-3 in both races. Eight additional IGFBP-3 SNPs were associated with plasma IGFBP-3, with generally consistent associations between races. Twelve IGF-I SNPs were associated with plasma IGF-I; however, associations were discordant between races, and were not consistent with diplotype findings. Uterine leiomyomata (fibroids) are responsible for substantial morbidity, especially among African Americans. Gene expression studies suggest IGF-I involvement in fibroid pathogenesis; IGFBP-3 may be important based on biological interrelations with IGF-I. IGF-I and IGFBP-3 polymorphisms have not been previously studied with fibroids. We evaluated the IGF-I and IGFBP-3 SNPs and estimated diplotypes from our first study in association with fibroid prevalence in our African American and Caucasian study population. Relatively precise prevalence differences (PD) with IGF-I and IGFBP- 3 SNPs were predominantly estimated among African Americans, including IGFBP-3 SNPs of rs9282734 (His158Pro) (PD = -0.130, 95% CI: -0.294, 0.034) and rs2475551 (splice site) (PD = 0.208, 95% CI: 0.095, 0.320) and IGF-I SNP rs35767 (promoter) (PD = 0.208, 95% CI: 0.095, 0.320). Associations with larger fibroids (2+ cm) were consistent or slightly weaker than with any fibroids. Diplotype associations were not consistent with SNP findings. Future research should validate our findings and examine additional genes within the IGF-I pathway.