Hypercortisolism is associated with impaired glucose tolerance and insulin resistance. For many years hydrocortisone 30 mg was the standard total daily replacement dose in adult hypopituitarism. The use of this conventional dose has now been shown to result in mild biochemical hypercortisolism and might contribute to the increased cardiovascular risk reported in hypopituitarism. The use of lower doses of hydrocortisone replacement therapy might prevent some of the adverse metabolic effects seen with conventional doses. In a randomized crossover study we assessed peripheral and hepatic insulin action in 15 ACTH-deficient patients with normal glucose tolerance on two occasions while receiving either a low-dose oral hydrocortisone replacement (LOR) therapy (15 mg at 0800, 5 mg at 1700) or a physiological hydrocortisone infusion (PHI), which achieved physiological serum cortisol concentrations. Exogenous glucose infusion rates required to maintain euglycaemia were similar for the LOR and the PHI protocols (26.2 +/- 0.4 vs. 23.8 +/- 0.6 micromol/kg/min, respectively). Endogenous glucose production was also similar (12.0 +/- 2.5 vs. 11.6 +/- 2.4 micromol/kg/min, respectively) and in the post-absorptive state suppressed to a similar extent following insulin (4.5 +/- 2.0 vs. 5.1 +/- 3.1 micromol/kg/min). Hydrocortisone replacement therapy at a dose of 15 mg with breakfast, 5 mg with evening meal does not increase peripheral or hepatic insulin resistance when compared to a hydrocortisone infusion designed to simulate physiological serum cortisol concentrations.