Plasma levels of insulin-like growth factor I (IGF-I) have been associated with risk of a number of cancers and other diseases. We examined the cross-sectional association of plasma IGF-I and IGF-binding protein 3 (IGFBP-3) levels with age, smoking, physical activity, and reproductive and menopausal factors in 1037 healthy women. Adjusted least-square mean hormone levels across categories of lifestyle factors were calculated by linear regression. Age was inversely associated with IGF-I levels. In multivariate analyses, a higher body mass index (BMI) was associated with higher IGFBP-3 levels (BMI <21 versus >/=29 kg/m(2), 3879 versus 4080 ng/ml; P for trend = 0.01). Current use of hormone replacement therapy (HRT) was associated with a lower IGF-I, with oral estrogen being associated with the lowest levels (non-use of HRT versus oral estrogen + progesterone versus oral estrogen: 181 versus 143 versus 116 ng/ml; P for all comparisons </= 0.005). Higher parity was also associated with lower levels of IGF-I (no pregnancies versus >/=4: 212 versus 180 ng/ml; P for trend = 0.003). We conclude that age and HRT use, particularly oral estrogen alone, were inversely associated with IGF-I levels. BMI was positively associated with IGFBP-3 levels. This is the first report of an inverse association of circulating IGF-I levels with parity. This association may represent one mechanism by which parity exerts its protective effect on some cancers.