Context: Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined. Objective: The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulin's hemodynamic effects was responsible for this effect. Design: We conducted an open interventional study between 2011 and 2013. Setting: The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia. Patients: Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied. Intervention: Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d. Main Outcome Measure: The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load. Results: Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3±0.2 vs 2.0±0.2; P=0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose. Conclusions: Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.