The aim of the present study was to examine corticosterone dynamics and its role in the pathogenesis of impaired wound healing in diabetes mellitus (DM). The streptozotocin-treated rat was used as an animal model for type I DM. A linear skin incision and subcutaneously implanted polyvinyl alcohol sponge disks were considered as wound-healing models. The data regarding corticosterone dynamics revealed diabetes-related increments in plasma corticosterone concentrations at various time intervals during the diurnal cycle (9:00 a.m., 12:00 noon, and 3:00 p.m.) Moreover, a reduction in the levels of hippocampal glucocorticoid receptors was also evident in this disease state. Immobilization-induced stress elevated plasma corticosterone levels in both control and 30-day diabetic rats. Although the diabetic rat seems capable of appropriately initiating a corticosterone stress response, it is dramatically impaired in its capacity to terminate it. A progressive decrease in collagen deposition on polyvinyl alcohol sponge and wounded skin tensile strength was seen as a function of the duration of diabetes. Similarly, polyvinyl alcohol sponges retrieved from 30-day diabetic rats also showed a marked reduction in the expression of mRNA transcripts for type I and type III collagen. A simulation of the impairment in wound-healing potential in DM was achieved by treating control animals with a supraphysiological dose of hydrocortisone. It is worthy of note that an endocrinological paradigm involving adrenalectomy and replacement therapy with hydrocortisone significantly improved the wound-related parameters, including collagen metabolism and wounded skin tensile strength in the streptozotocin diabetic rats. Overall, our data provide evidence that the diabetic state is associated with hypercortisolemia and that this phenomenon may contribute to impaired wound healing in DM.