Circulating insulin-like growth factors (IGFs) and their binding proteins have been associated with increased risk of breast, prostate, colon, and lung cancer. To examine the association of IGFs and endometrial cancer risk, we measured the plasma levels of IGF-1, IGF-2, and IGF binding protein 3 (IGFBP-3) by ELISA in 80 women with endometrial cancer and 80 age-matched control subjects with no history of cancer. Mean plasma levels of IGF-2 were significantly higher in women with cancer versus controls (670 ng/ml versus 380 ng/ml, P < 0.001). In contrast, significantly lower mean plasma levels of IGF-1 (155 mg/ml versus 185 ng/ml, P < 0.01) and IGFBP-3 (1703 ng/ml versus 2170 ng/ml, P < 0.001) were observed among cases compared to the control group. Women in the highest quartile of IGF-2 were found to have 9.67 (95% confidence interval 3.29-28.43) times the risk of endometrial cancer than women in the lowest quartiles. Women in the highest quartile of IGFBP-3 were associated with a significantly decreased risk for developing endometrial cancer (odds ratio = 0.23, 95% confidence interval 0.09-0.60). These data suggest that increased plasma levels of IGF-2 and decreased levels of IGFBP-3 are associated with an increased risk of endometrial cancer. Further validation of these results is needed to determine the potential usefulness of risk assessment.