Age-related macular degeneration (AMD) is a degenerative retinal disease and one of major causes of irreversible vision loss. AMD has been linked to several pathological factors, such as oxidative stress and inflammation. Moreover, Aβ (1-42) oligomers have been found in drusen, the extracellular deposits that accumulate beneath the retinal pigmented epithelium in AMD patients. Hereby, we investigated the hypothesis that treatment with 1,25(OH) ₂ D ₃ (vitamin D ₃ ) and meso-zeaxathin, physiologically present in the eye, would counteract the toxic effects of three different insults on immortalized human retinal pigmented epithelial cells (ARPE-19). Specifically, ARPE-19 cells have been challenged with Aβ (1-42) oligomers, H ₂ O ₂ , LPS, and TNF-α, respectively. In the present study, we demonstrated that the combination of 1,25(OH) ₂ D ₃ and meso-zeaxanthin significantly counteracted the cell damage induced by the three insults, at least in these in vitro integrated paradigms of AMD. These results suggest that combination of 1,25(OH) ₂ D ₃ and meso-zeaxathin could be a useful approach to contrast pathological features of AMD, such as retinal inflammation and oxidative stress.