PURPOSE: The role of the antioxidant enzyme glutathione peroxidase-1 (GPx1) in protecting the retina against photo-oxidative damage was investigated in GPx1-deficient and wild-type mice. METHOD: Albino GPx1-deficient and age-matched wild-type mice were examined. Baseline electroretinograms (ERGs) were recorded. Thereafter, mice were exposed to intense light for 12 hours. After a 24-hour recovery in darkness, post-light-insult ERGs were recorded and compared with baseline. Structural effects of light insult were evaluated by retinal histology. Antioxidant expression was investigated by quantitative reverse transcription-PCR (qRT-PCR). RESULTS: Light insult significantly affected ERG responses, with reduced a- and b-wave amplitudes. Structurally, photoreceptor layers were predominantly affected. As expected, GPx1 expression was negligible in GPx1-deficient mice but was upregulated in wild-type mice in response to light insult. Similarly, hemeoxygenase-1 and thioredoxin-1 expression increased significantly in wild-type retinas after light exposure. Catalase, GPx isoforms (GPx2 to -4), peroxiredoxin-6, glutaredoxin-1, and thioredoxin-2 expression was unaffected by GPx1 deficiency and light insult, whereas significant increases in glutaredoxin-2 occurred in non-light-exposed (baseline) GPx1-deficient retinas. Compared with baseline wild-type retinas, lipid peroxidation (TBARS assay), an indicator of oxidative stress, was elevated in baseline GPx1-deficient retinas. Unexpectedly, the light insult induced diminution of retinal function, in terms of ERG amplitude, and structural damage was significantly greater in wild-type than in with GPx1-deficient retinas. CONCLUSIONS: The data showing increased oxidative damage in baseline GPx-deficient retina give rise to the hypothesis that increased oxidative stress provides a "preconditioning" environment in which protective mechanisms paradoxically render GPx1-deficient retinas less vulnerable to light-induced oxidative damage. This study identified glutaredoxin-2 as a potential candidate.