BACKGROUND Cellular proliferation, as measured by S-phase fraction, is an important predictor of breast cancer prognosis. The insulin-like growth factors (IGFs) have been shown to regulate proliferation in both normal and neoplastic cells by interacting with specific cell surface receptors. In addition to these receptors, high-affinity extracellular binding proteins also modulate IGF action. These insulin-like growth factor-binding proteins (IGFBPs) could influence breast cancer growth and, like other biological parameters of proliferation, could be related to prognosis. OBJECTIVE To test whether IGFBP expression was related to other biological parameters and disease-free survival, we measured IGFBP expression in 238 lymph node-negative primary breast cancer specimens. METHODS Proteins were extracted from breast cancer specimens and analyzed by semiquantitative IGF-I ligand blotting for IGFBP expression. IGFBP expression levels were compared to tumor size, age, S-phase fraction, DNA ploidy, and estrogen and progesterone receptor expression by Spearman correlation. RESULTS Binding protein (BP)-2, BP-3, BP-4, and BP-5 were identified in breast cancer extracts. Estrogen receptor expression was positively correlated with BP-2 (Spearman correlation coefficient, rs = .262; P = .0001), BP-4 (rs = .313; P = .0001), and BP-5 (rs = .242; P = .0002). Similar correlations between progesterone receptor and BP-2, BP-4, and BP-5 were also found. BP-3 was inversely correlated with age (rs = -.251, P = .0001). BP-4 was weakly inversely correlated with tumor size (rs = -.141; P = .0295) and S-phase fraction (rs = -.216; P = .0025). Since tumor size and S-phase fraction are powerful predictors of prognosis in node-negative breast cancer, we examined the value of BP-4 as a predictor of disease-free survival. When stratified by tumor size, patients with large (> 2 cm) tumors that expressed low levels of BP-4 had improved survival when compared with patients with large tumors and high BP-4 levels (P = .001). CONCLUSIONS IGFBPs can be detected in breast cancer specimens, and their level of expression correlates with other known biological parameters of breast cancer. Large tumors with low levels of BP-4 have relatively favorable prognoses. CONCLUSIONS These data suggest that the IGFBPs may play a role in breast cancer biology and that BP-4 levels, analyzed in conjunction with tumor size, may have prognostic significance.