Retinitis pigmentosa (RP) is a major source of blindness caused by a large variety of mutations that lead to the death of rod photoreceptors. After rods die, cones gradually die from progressive oxidative damage. Several types of antioxidant formulations have been shown to reduce cone cell death over a relatively short-time frame, but in order for this strategy to be translated into a new treatment for patients with RP, prolonged effects will be needed. In this study, we determined that orally administered N-acetylcysteine (NAC) reduced cone cell death and preserved cone function by reducing oxidative damage in two models of RP, rd1+/+ and rd10+/+ mice. In rd10+/+ mice, supplementation of drinking water with NAC promoted partial maintenance of cone structure and function for at least 6 months. Topical application of NAC to the cornea also reduced superoxide radicals in the retina and promoted survival and functioning of cones. Since oral and/or topical administration of NAC is feasible for long-term treatment in humans, and NAC has a good safety profile, it is reasonable to consider clinical trials to evaluate the effects of prolonged treatment with NAC in patients with RP. J. Cell. Physiol. 226: 1843–1849, 2011. © 2010 Wiley-Liss, Inc.