Insulin-like growth factor binding protein-1 (IGFBP-1) modulates the metabolic and mitogenic actions of the IGF peptides. Previous studies have established insulin as the major regulator of plasma IGFBP-1 in humans, acting to suppress hepatic IGFBP-1 synthesis. In this study, we investigated the regulation of plasma IGFBP-1 by cortisol in humans, independent of insulin. Following an overnight fast, six healthy adult volunteers received a euglycemic pancreatic clamp (somatostatin, 0.12 microgram.kg-1.min-1; GH, 3 ng.kg-1.min-1; insulin, 0.05 mU.kg-1.min-1) to block endogenous insulin secretion and to control glucose and plasma hormone concentrations at desired levels. Three hours after the initiation of the pancreatic clamp, each subject received an additional 360 min infusion of either cortisol (2 micrograms.kg-1.min-1) or saline on separate occasions and in random order. Plasma cortisol concentrations increased from 220 to 970 nmol/l during the cortisol infusion. Insulin concentrations were maintained at approximately 30 pmol/l throughout saline and cortisol infusions. Plasma IGFBP-1 concentrations increased threefold in response to hypoinsulinemia, reaching plateau values of approximately 140 micrograms/l with saline infusion. During cortisol infusion, IGFBP-1 levels increased to approximately 300 micrograms/l. Over the 360 min study period, the integrated response of plasma IGFBP-1 to cortisol infusion was 314% greater than to saline infusion (p < 0.01). Our data confirm that, under conditions of hypoinsulinemia, cortisol is a significant modulator of plasma IGFBP-1 in humans.