Insulin-like growth factors (IGFs) and estrogens are essential hormones regulating the growth and differentiation of mammary cells. Studies have shown that IGFs and estrogens are strong mitogens for breast cancer cells and that high circulating IGF-I and estrogens are risk factors of breast cancer. Laboratory experiments further indicate that these hormones act synergistically on the pathogenesis of breast cancer. Estrogens increase the effect of IGF-I on breast cancer cells by stimulating the expression of IGF-I and IGF-I receptor; IGFs enhance the action of estrogens by regulating the production of estrogen receptor. Furthermore, the two systems have substantial signal transduction cross-talk. Despite the laboratory indications, there is no epidemiological evidence in support of the joint effect of IGFs and estrogens on breast cancer risk. To test this hypothesis in human populations, we compared plasma levels of IGFs and sex steroid hormones among 300 incident breast cancer patients and 300 age- and menopause-matched control women derived from a large population-based case-control study conducted in Shanghai, China between 1996 and 1998. Fasting morning blood samples were measured for plasma concentrations of IGF-I, IGF-II, IGF-binding protein (IGFBP)-3, estradiol, estrone, estrone sulfate, testosterone, and dehydroepiandrosterone sulfate using commercial immunoassay kits. Levels of these hormones were classified into two groups based on the median levels in the control group and combined between IGFs and steroid hormones. Conditional logistic regression analysis was performed to examine the association of breast cancer risk with the combined variables of sex steroids and IGFs. A synergistic effect on breast cancer risk was suggested for IGF-I or IGFBP-3 with estrone or testosterone among both pre- and postmenopausal women. Compared with premenopausal women with low circulating levels of both IGF-I and estrone, the odds ratios were 1.21 [95% confidence interval (CI), 0.61-2.40] for high estrone, 1.50 (95% CI, 0.77-2.93) for high IGF-I, and 2.30 (95% CI, 1.21-4.37) for both high estrone and high IGF-I. Similar patterns of association were also seen for IGF-I with testosterone as well as for IGFBP-3 with estrone or testosterone, and some of the interactions were statistically significant or borderline significant (P < 0.10). No joint effects were found for IGF-I or IGFBP-3 with estradiol or estrone sulfate. In conclusion, the study suggests a possible synergy between IGF peptide hormone and sex steroid hormones, including both estrogen and androgen, in relation to breast cancer risk.