OBJECTIVE To study the apoptotic mechanism involved in our model of light-induced retinal degeneration. METHODS Rats were injected intravitreally with PBS, 2% dimethyl sulfoxide (DMSO), caspase inhibitor Z-VAD-FMK (1.06 mM), Z-YVAD-FMK (0.16 mM), or Z-DEVD-FMK (2 mM) before they were placed in constant light (3400 lux) for 24 hours. Additional controls included rats that were uninjected or were punctured with a dry needle. Electroretinograms were recorded before injection and 1 day after the cessation of exposure to constant light. A group of rats was killed for apoptotic cell detection in the outer nuclear layer. Fifteen days later, the remaining rats were killed for histology, and the outer nuclear layer (ONL) thickness was measured. Caspase-1, caspase-3, and calpain activities were measured before and 1 day after exposure to the damaging light. RESULTS ZVAD, YVAD, and DEVD inhibited caspase-1 and -3 activities, but not calpain activity, from the beginning and up to 1 day after light exposure. In untreated, dry needle-punctured, PBS, DMSO, and YVAD groups, light exposure significantly reduced retinal function and ONL thickness and increased by 51-fold the number of apoptotic cells. ZVAD and DEVD preserved retinal function to 86% and 78%, respectively, and reduced by three times the number of apoptotic photoreceptors. ONL thickness was more preserved in ZVAD (to 72%) than in DEVD (to 56%). CONCLUSIONS In the authors' model of retinal degeneration, photoreceptor cells die through a caspase-dependent mechanism. However, the molecular events involved during and after light exposure seemed to implicate different proteases.