Background and Objective: To evaluate the possibility of oxygen radical damage in the skin after He-Ne laser irradiation according to dose intensity and time. Study Design/Materials and Methods: The He-Ne laser (lambda = 632.8, 10 mW) was used on the skin of mice with 1, 3, and 5 joule (J/cm(2)) dose rates for 1, 5, and 7 days in each case, and the results were compared with normal and anesthetic nonirradiated skins. The efficacy was determined by the formation of thiobarbituric acid-reactive substances (TBARS) in a 10-minute period and expressed as a concentration of malondialdehyde (MDA) from the lipid peroxidation of epidermal tissue, and total superoxide dismutases (SODs) and catalase activities, correlated with histologic biopsies. Results: Data from epidermal SODs, catalase activity and the degree of lipid peroxidation at law-power radiation showed that repeated exposure had led to the induction of free radical damage and of epidermal changes as confirmed by microscopic study. The application of the He-Ne laser at 1, 3, and 5 J intensity for 5 days caused a gradual increase in the SODs and catalase activities, while the levels of TEARS were slightly decreased in the mouse epidermis. However, these patterns were reversed after 3 and 5 J irradiations for 5 and 7 days laser treatment. Furthermore, microscopic examinations revealed that the laser-irradiated skin changed the release of stratum granule from epidermis to hair follicle, and produced blood vessel thrombosis of the dermal capillary plexus. Conclusion: The presence of lipid peroxidation in the hairless mouse skin after exposure to He-Ne laser energy intensity of over 3 J for over 5 days was demonstrated. This lipid peroxidation could have been generated from oxygen free radicals. The histologic and oxidative enzymatic correlations on lipid peroxidation in the skin have provided a better understanding of He-Ne laser therapy-tissue interactions. It is possible to take advantage of these findings to evaluate pathologic skin conditions and effective laser dosage more efficiently. Lasers Surg. Med. 27:420-426, 2000. (C) 2000 Wiley-Liss, Inc.