Context: Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile. Objective: The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets. Design and Setting: We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers. Patients: The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM). Intervention: The same daily dose of hydrocortisone was administered as OD dual-release or TID. Main Outcome Measure: We evaluated cortisol pharmacokinetics. Results: Compared with conventional TID, OD provided a sustained serum cortisol profile 0–4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = −0.7 kg, P = 0.005), systolic blood pressure (difference = −5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: −2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = −0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004). Conclusion: The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.