INTRODUCTION: Patients who need glucocorticoid replacement in both primary and secondary adrenal insufficiency have the choice of either once daily prednisolone or thrice daily hydrocortisone. A recent European study found no difference between prednisolone and hydrocortisone users in several markers including glucose, weight, body mass index (BMI), systolic and diastolic blood pressure and waist circumference, although an increase in cholesterol and low density lipoprotein (LDL) was suggested in a subgroup of these patients. The aim of this study was to expand the evidence base for the use of these agents as replacement therapy. METHOD: Data from 82 patients on hydrocortisone and 64 patients on prednisolone for adrenal insufficiency at Imperial College Healthcare Trust were analysed. RESULTS: There was no significant difference in total cholesterol, LDL levels or any other risk factors between hydrocortisone and prednisolone patients. Prednisolone was subjectively significantly more convenient than hydrocortisone (p=0.048). CONCLUSIONS: Prednisolone once daily is more convenient than hydrocortisone thrice daily, and there is no difference in the markers of cardiovascular risk measured. Because prednisolone mimics the circadian rhythm better than other glucocorticoids, it should be considered as an alternative to hydrocortisone for adrenal insufficiency.