The purpose of this study was to investigate the presence of oxidative DNA damage in the photoreceptors of the rd1 mouse, an animal model for retinitis pigmentosa, and to determine if antioxidants could delay the progress of photoreceptor cell death. Retinas of rd1 mice and congenic wild type controls were examined for DNA oxidation and fragmentation. To study the rescue effect of antioxidants on retinal degeneration, rd1 retinas were studied in vitro and in vivo using lutein, zeaxanthin, alpha lipoic acid and reduced l-glutathione. For the in vitro studies, antioxidants were added to the culture medium. For the in vivo studies, postnatal day (PN3) pups of rd1 mice were fed antioxidants either individually or in combination and control rd1 animals received vehicle alone. Histological evaluation was performed using hematoxylin/eosin and avidin staining, as well as terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Many of the rd1 rod photoreceptors at PN11 displayed oxidative DNA damage and TUNEL positive reaction which co-localized in a subset of rod photoreceptors. Avidin-labeled rod photoreceptors were more abundant than the TUNEL positive photoreceptors of the rd1 mouse, indicating that oxidative DNA damage precedes fragmentation. The number of TUNEL positive and avidin positive cells was considerably decreased upon treatment with the combination of the antioxidants. Rescue of rd1 photoreceptors was significant at PN18 and PN17, respectively, in the in vitro and in vivo studies. In conclusion individual antioxidants had no significant rescue effect but the combination slowed down the rd1 rod photoreceptor degeneration, indicating an additive or synergistic effect.