Abstract Hyperbaric oxygen therapy (HBOT) is used for anumber of applications, including the treatment of diabeticfoot ulcers and CO poisoning. However, we and others haveshown that HBOT can mobilize cellular antioxidantdefenses, suggesting that it may also be useful under cir cumstances in which tissue protection from oxidative dam age is desired. To test the protective properties of hyperbaric oxygen (HBO) on a tissue level, we evaluated the ability ofa preconditioning treatment regimen to protect cutaneous tissue from UV-A-induced oxidative damage. Three groups of hairless SKH1-E mice were exposed to UV-A 3 days perweek for 22 weeks, with two of these groups receiving an HBO pretreatment either two or four times per week. UV-A exposure increased apoptosis and proliferation of the skintissue, indicating elevated levels of epithelial damage and repair. Pretreatment with HBO significantly reduced UV-A induced apoptosis and proliferation. A morphometric anal ysis of microscopic tissue folds also showed a significant increase in skin creasing following UV-A exposure, which was prevented by HBO pretreatment. Likewise, skin elas ticity was found to be greatest in the group treated with HBO four times per week. The effects of HBO were also apparent systemically as reductions in caspase-3 activity andexpression were observed in the liver. Our findings support a protective function of HBO pretreatment from a direct oxidative challenge of UV-A to skin tissue. Similar protec tion of other tissues may likewise be achievable.