Purpose: Induction of oxidative stress has been implicated in UV-induced melanoma.We sought to determine whether the antioxidant N-acetylcysteine (NAC) could be safely administered to protect melanocytic nevi from the oxidative stress resulting from acute UV exposure. Experimental Design: Patients at increased risk for melanoma were recruited from a screening clinic. Induction and detection of oxidative stress (reactive oxygen species and glutathione depletion) was optimized in nevi following ex vivo UV irradiation. Nevi were removed from patients before, and following, oral ingestion of a single (1,200 mg) dose of NAC, and then these nevi were UV irradiated (4,000 J/m 2 ). Results: Oxidative stress was induced in nevi 24 to 48 hours following ex vivo UV irradiation. A single oral dose of NAC was well tolerated in all patients (n = 72). Basal levels of reduced glutathione and the NAC metabolite cysteine were well correlated between similar-appearing nevi from the same patient and were significantly increased in nevi removed 3 hours after NAC ingestion compared with nevi removed before drug ingestion. In approximately half (9 of 19) of patients tested, UV-induced glutathione depletion was attenuated in the postdrug (compared with predrug) nevus. Conclusions: NAC can be safely administered to patients for the purpose of modulating UV-induced oxidative stress in nevi. This study suggests the feasibility of patients taking NAC prophylactically before acute UV exposure, to prevent pro-oncogenic oxidative stress in nevi and ultimately reduce long-term melanoma risk. (Clin Cancer Res 2009;15(23):7434-40) Melanoma is a potentially lethal form of skin cancer, which unfortunately in recent years has seen a dramatic increase in incidence that has not been matched by the development of effective therapies for patients with advanced disease (1). Although melanoma may arise directly from isolated melanocytes, a significant fraction of melanomas develop from nevi (or moles; ref. 2), which represent congenital or acquired clonal neoplasms of melanocytes (3). Nevi are far less prevalent on sun-protected skin and their development is related to sun exposure (4), which also is the major environmental risk factor for melanoma (5). Patients can reduce the potentially harmful effects of UV by limiting sun exposure and/or using sunscreen, although some studies suggest that sunscreen use may increase melanoma risk (6), perhaps due to increased sun exposure in sunscreen users (7). Although sunscreens are designed to prevent sunburn, it is unclear whether they protect against all possible carcinogenic effects of UV exposure. Given these considerations, and the fact that most patients do not apply sunscreens properly (8), reliance on sunscreen alone may be inadequate and there is need for additional preventive strategies.UV in sunlight is a potent inducer of reactive oxygen species (ROS) in the skin (9), which may damage intracellular constituents and deplete vital reductants such as glutathione (GSH; ref. 10). Sustained oxi...