Circulating concentrations of IGF-I and IGFBP-3 are associated with risk of pre-menopausal breast cancer. Racial differences in levels of these factors have been reported, and determinants of IGF-I and IGFBP-3 levels within racial and ethnic groups are unclear. In this study we examine genetic, anthropometric, diet, and lifestyle factors that may predict serum levels of IGF-I and IGFBP-3 among Hispanic and non-Hispanic white women. A sample of healthy controls participating in the SHINE (Southwest Hormone, Insulin, Nutrition, and Exercise Study) case-control breast cancer in Arizona, Colorado, New Mexico, and Utah were included in these analyses. Subjects included 210 Hispanic and 284 non-Hispanic white women. Hispanic women had significantly lower levels of IGFBP-3 (mean=3764.3 mcg/ml) after adjusting for age, body size, physical activity, menopausal status, and dietary factors than non-Hispanic white women (mean = 4058.0 mcg/ml; p<0.01). The CC genotype of the -202 A>C polymorphism of the IGFBP3 gene was associated with lower IGFBP-3 levels in both ethnic groups. The frequency of the IGFBP3 C allele differed between Hispanic (0.65) and non-Hispanic white women (0.53), but serum levels of IGFBP-3 were lower for Hispanic women than non-Hispanic after accounting for IGFBP3 genotype. Body size indicators, vigorous physical activity, and dietary factors appeared to influence serum levels of IGF-1 and the ratio of IGF-1 to IGFBP-3 in pre-menopausal women more than in post-menopausal women. On the other hand, using aspirin/NSAIDs appeared to increase IGFBP-3 levels significantly among pre-menopausal Hispanic women. Results from this study suggest that differences in IGFBP-3 levels exist in Hispanic and non-Hispanic white women. These differences could be due to the combined effects of genetic and behavioral factors which could account for ethnic differences in the risk of breast cancer and other chronic diseases.