The photodermatosis in erythropoietic protoporphyria (EPP) is caused by the accumulation of photosensitizing protoporphyrin (PP) in the skin, due to a defect in ferrochelatase, the enzyme that inserts ferrous iron into PP to form heme. Hydroxyl radical (.OH) and singlet oxygen generation with subsequent lipid peroxidation are thought to play a major role in the pathogenesis of the photodermatosis in EPP. Hydrogen peroxide (H2O2) can generate .OH in the Haber-Weiss as well as the Fenton reaction, and is thus a potentially harmful intermediate in the photoreduction of O2. The use of oxyradical scavengers, such as beta-carotene, has been reported to be beneficial in the treatment of EPP photodermatosis. In this study, N-acetylcysteine (NAC) 1800 mg/day was used for 3 reasons: (i) its -SH groups directly scavenge H2O2; (ii) ferrochelatase can be activated by sulfhydryl groups; (iii) NAC was reported to upregulate the glutathione redox system, which is a major endogenous anti-oxidant system. However, in a double-blind crossover placebo controlled study on 6 EPP patients, we could neither demonstrate an effect through photosensitivity tests, nor on light hypersensitivity as reported by the patients. This dosage of NAC could not increase reduced glutathione and did not affect the red blood cell PP content nor the excretion of PP in the feces. Neither were adverse effects observed. We conclude that the oral administration of NAC, in the relatively low dose used here, is not effective in the treatment of photodermatosis in EPP.