Chronic exposure to sunlight plays a role in skin aging and carcinogenesis. The molecular mechanisms of photodamage by ultraviolet A, the sunlight's major ultraviolet constituent, are poorly understood. Here we provide evidence that advanced glycation end products on proteins are sensitizers of photo-oxidative stress in skin cells. Glycation is a process of protein damage by reducing sugars and other reactive carbonyl species leading to the formation of advanced glycation end products, which accumulate on long-lived proteins such as dermal elastin and collagen during skin aging. Growth inhibition as a result of advanced glycation end product photosensitization of ultraviolet A and solar-simulated light was demonstrated in human keratinocytes and fibroblasts. Using advanced glycation end product bovine serum albumin and advanced glycation end product collagen as model photosensitizers, ultraviolet A-induced formation of H2O2 was identified as the key mediator of skin cell growth inhibition as evidenced by complete protection by catalase treatment and equivalent growth inhibition of unirradiated cells treated with pre-irradiated advanced glycation end product protein. D-penicillamine protected against advanced glycation end product-photosensitized growth inhibition even when added following irradiation, suggesting the feasibility of therapeutic approaches for protection against skin ultraviolet A damage. Photosensitized growth inhibition increased with the degree of advanced glycation end product modification paralleled by the amount of H2O2 formed upon solar-simulated light irradiation of the protein. Photosensitization was not observed using bovine serum albumin modified with the major advanced glycation end product, Nepsilon-carboxymethyl-L-lysine, ruling out effects of cellular advanced glycation end product receptor (RAGE) stimulation. In contrast to bovine serum albumin, unglycated collagen showed photosensitization in CF3 fibroblasts and generation of H2O2 upon solar-simulated light irradiation. This study supports the hypothesis that advanced glycation end product-modified proteins are endogenous sensitizers of photo-oxidative cell damage in human skin by ultraviolet A-induced generation of reactive oxygen species contributing to photoaging and photocarcinogenesis.