Technical Abstract: C57Bl/6 mice were subjected to hindlimb unloading (HU) for a period of three weeks to determine the possible effects on epithelial wound healing. A standardized corneal epithelial wound was performed and parameters of the inflammatory response and re-epithelialization were analyzed over an observation period of 96 hours. Wound closure was significantly retarded in mice during HU with re-epithelialization being delayed by approximately 12 hours. Both epithelial migration and cell division were significantly depressed and delayed. The inflammatory response to epithelial wounding was also significantly altered during HU. Neutrophils as detected by the Gr-1 marker were initially elevated above normal levels prior to wounding and during the first few hours afterwards, but there was a significant reduction in neutrophil response to wounding at times where neutrophil influx and migration in controls were vigorous. A similar pattern was seen with CD11b+CD11c+ cells (monocyte lineage). Langerhans cells (LC) are normally resident within the peripheral corneal epithelium. They respond to injury by initially leaving the epithelial site within 6 hours and returning to normal levels by 96 hours, 2 days after re-epithelialization is complete. During HU this pattern is distinctly different, with LC numbers slowing diminishing, reaching a nadir at 96 hours, significantly below normal. Evidence for systemic effects of HU is provided by findings that collagen deposition within subcutaneous sponges was significantly reduced during HU.