Our purpose was to evaluate which factors regulate insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in preterm fetuses.We studied 76 singleton births between 25 and 36 weeks of gestation. Forty-nine pregnancies were complicated by hypertensive disease; 24 pregnancies were complicated by preterm labor or preterm rupture of membranes; and antenatal glucocorticoids were given in 49 pregnancies. Pathology reports showed infarct(s) or hematoma(s) in 31 of 69 placentas. We recorded blood gas values in umbilical artery and vein and measured glucose, C-peptide, and insulin-like growth factor-I and insulin-like growth factor binding protein-1 concentrations in umbilical vein.Birth weight correlated with umbilical vein insulin-like growth factor-I (r = 0.68, P 25th percentile. Two-factor analysis of variance showed that umbilical vein insulin-like growth factor-I was determined by gestational age (P =.0004) and birth weight percentile (P <.0001), whereas insulin-like growth factor binding protein-1 was not affected by gestational age. Umbilical vein C-peptide was highly correlated with insulin-like growth factor binding protein-1 (r = -0.55, P <.0001), but not insulin-like growth factor-I, levels. Blood gas values in umbilical artery and vein, particularly umbilical artery PO (2), were correlated with umbilical vein insulin-like growth factor-I and insulin-like growth factor binding protein-1 (r = 0.51 and -0.48, respectively; P <.0001); changes in insulin-like growth factor-I and insulin-like growth factor binding protein-1 occurred at umbilical artery PO (2) <14.8 mm Hg. Multiple regression analysis showed that umbilical vein insulin-like growth factor-I was predicted by umbilical artery PO (2), gestational age, and the presence of placental infarcts/hematomas (R (2) of model = 0.58, P <.0001), and umbilical vein insulin-like growth factor binding protein-1 by umbilical vein C-peptide, umbilical artery PO (2), and placental infarcts/hematomas (R (2) = 0.49, P <.0001).In the preterm fetus, circulating insulin-like growth factor-I is related to gestational age and the in utero growth potential, whereas insulin-like growth factor binding protein-1 is related only to the in utero growth potential. The PO (2) is a robust determinant of both insulin-like growth factor-I and insulin-like growth factor binding protein-1 levels; hypoxia may restrain fetal growth through its effects on the insulin-like growth factor/insulin-like growth factor binding protein axis. Insulin is a powerful determinant of insulin-like growth factor binding protein-1, but not insulin-like growth factor-I, concentrations in the preterm fetus.