Nerve regeneration in diabetes is essential for reversal of neuropathy as well as the recovery of nerves from injury due to acute nerve compression and entrapment. Endoneural hypoxia due to hyperglycemia-induced blood flow reductions is observed early in the course of diabetes, and the resultant ischemia plays a role in the diminished neural regeneration. Hyperbaric oxygen therapy is capable of producing tissue hyperoxia by raising oxygen tensions in ischemic tissues, and was shown to be beneficial in the reversal of experimental ischemic neuropathy. In this study, an experimental diabetes model was used to evaluate the functional and histomorphological effects of hyperbaric oxygen therapy on early diabetic nerve regeneration. Our results indicate that there is significant histomorphological impairment of nerve regeneration, even in very early stages of diabetes. However, no beneficial effects of hyperbaric oxygen therapy could be demonstrated at this stage. (C) 2004 Wiley-Liss, Inc.