As evidence builds for cancer risk associated with insulin-like growth factors (IGFs) and their binding proteins (BPs), capitalizing on such associations for cancer prevention requires identifying the determinants of IGF levels. We measured plasma IGF-I, IGF-II, and IGF BP-3 in a cross-section of 210 men and 171 postmenopausal women enrolled in research as healthy controls. Using linear regression adjusted for age and ethnicity, we evaluated associations between IGF and IGF BP levels and gender, height, body mass index (BMI), smoking, caloric intake, physical activity, and reproductive factors. As expected, women using hormone replacement therapy (HRT) recently had significantly lower IGF-I levels than nonusers. Overall, IGF-I and IGF BP-3 levels did not differ by gender, although men had significantly higher molar ratios of IGF-I to IGF BP-3 and lower plasma IGF-II than women without recent HRT use. For men, BMI was a better predictor of IGF-I levels than height, whereas for women, height was more important. Lower IGF-II levels for both genders were associated with higher BMI and lower physical activity. Lower physical activity was associated with lower IGF BP-3 levels among men. Miscarriage number and menopausal age were positively associated with IGF BP-3 levels. HRT use strongly depressed IGF-I levels among smokers, and additional analysis revealed no remarkable associations. Caloric intake was negatively associated with IGF-I levels among men. Results for ratios of IGF-I and IGF-II to IGF BP-3 generally reflected those for IGF-I and IGF-II levels, respectively. In conclusion, whereas some traditional cancer risk factors were associated with IGF levels, altogether, they accounted for <15% of the total variability in plasma levels for each IGF, suggesting that other factors influence IGF levels.