Retinal pigment epithelial (RPE) cells are largely postmitotic. They continuously phagocytose the outer tips of the photoreceptor outer segments (POS). Over the life span of an individual, this activity results, although surprisingly slowly, in the intralysomal accumulation of lipofuscin, or age-pigment. Native lipofuscin shows orange-red autofluorescence when exposed to blue light. The loss of energy resulting from the conversion of excitatory blue light into emitted orange-red light may induce photo-oxidative reactions. We exposed neonatal rabbit RPE cells in culture to purified POS from cow eyes. The material were either native or peroxidized by irradiation with UV-light before being added to the RPE cultures. Lipofuscin accumulation was studied by transmission electron microscopy and measured by microfluorometric registration of its autofluorescence. Cells exposed to peroxidized POS accumulated much more lipofuscin than those exposed to native POS, indicating that peroxidized outer segments are not digestable by lysosomal enzymes. Furthermore, lipofuscin-loaded RPE cells were considerable more sensitive to visible blue light than unloaded control cells. The former ones showed lysosomal membrane destabilization with ensuing leakage of lytic enzymes and eventually cell death. We suggest that photo-oxidation of lysosomal membranes surrounding accumulated lipofuscin may be of importance for the development of age-related macular degeneration.