High levels of circulating insulin-like growth factor-I (IGF-1), and its major binding protein (IGFBP-3) at premenopausal ges have been associated with an increased breast cancer risk. We conducted a cross-sectional study (215 premenopausal women and 241 after natural menopause) nested within the Guernsey prospective studies to examine the relationship between the IGF system and mammographic features of the breast. The mammographically dense area in he breast increased with increasing serum levels of IGF-I P for linear trend, P-t = 0.05), IGF-II (Pt = 0.08), and IGFBP-3 P-t = 0.01) only in premenopausal women. lGF-II and IGFBP-I serum levels were associated with increases in the mammgraphically lucent area in both premenopausal (P-t = 0.01 and 0.04, respectively) and postmenopausal women (Pt < 0.001 for both), but these associations were no longer statistically significant after adjustment for body mass index and waist circumference. Neither the IGF-I/IGFBP-3 nor the IGF-II/IGFBP-3 molar ratio was associated with any of these mammographic features. The number of A alleles at a polymorphic locus in the promoter region of the IGFBP-3 gene was associated with increasing mean IGFBP-3 levels in both premenopausal (P-t = 0.01) and postmenopausal (P-t < 0.001) women but not with mammographically dense area. These results support the hypothesis that the IGF system may affect the amount of mammographically dense tissue in premenopausal women, possibly by promoting cell proliferation and inhibiting apoptosis in the fibroglandular tissue. The findings also show strong relations between IGF-II and IGFBP-3 levels and the amount of mammographically lucent tissue, reflecting the associations between body adiposity and amount of fat tissue in the breast and between body adiposity and circulating levels of these growth factors.