Background: Low dehydroepiandrosterone sulfate (DHEAS) levels and a high cortisol/ DHEAS ratio are associated with higher mortality in elderly, dialyzed, and immunocompromised patients. The role of these hormones in patients with hypoglycemia unawareness (hypo) or in pancreas or islet recipients treated by glucocorticoid-free immunosuppressive regimen (IS) has not been studied.Objective: The aim of this study was to determine the effects of IS and of recurrent hypoglycemia on DHEAS and adrenocorticotropic hormone (ACTH) levels in patients with type-1 diabetes (T1DM). Methods: A case control, cross-sectional analysis of patients in a prospective database enrolled 84 patients with T1DM. They were divided into 4 groups of 21 subjects each: 1) islet or pancreas recipients with hypoglycemia who are IS (hypo +, IS +); 2) pancreas and kidney transplant recipients without insulin or hypoglycemia (hypo -, IS +); 3) T1DM patients with hypoglycemia (hypo +, IS -); and 4) T1DM patients without hypoglycemia (hypo -, IS -). Results: DHEAS and ACTH levels were significantly decreased in patients with hypoglycemia (P = 0.0002 and P = 0.0001, respectively) as well as in those with IS (P = 0.0497 and P < 0.001, respectively) compared to those without hypoglycemia or IS. The influence of hypoglycemia unawareness on DHEAS levels was stronger than that of immunosuppression (P < 0.10). Conclusion: Low DHEAS and ACTH levels represent an additional component of hypoglycemia unawareness syndrome and they remain low in patients receiving glucocorticoid-free immunosuppression. DHEAS may serve as a marker, the importance of which remains unclear, but deserves attention.