Retinal pigment epithelium (RPE) are specialized multifunctional cells indispensable for maintenance of vision. Dysfunction and death of the RPE cells is implicated in the genesis and progression of age-related macular degeneration (AMD). Oxidative stress and resulting cellular damage plays a critical mechanistic role in AMD pathogenesis. Oxidized low-density lipoprotein (oxLDL), derived from LDL in a pro-oxidative environment, is found adjacent to the RPE as part of drusen, extracellular deposits that are a characteristic clinical feature of AMD. OxLDL is cytotoxic and oxLDL-induced oxidative damage may contribute to functional impairment of the RPE. Therefore, knowledge of how the RPE respond to oxLDL exposure is important to understand the mechanisms underlying RPE dysfunction and death associated with AMD. The objective of this study was to characterize alterations in the RPE proteome triggered by exposure to non-cytotoxic levels of oxLDL. Protein identification and quantification were performed with a high -resolution LC-MS/MS-based proteomics workflow. In total, out of the ca 3000 RPE proteins quantified, oxLDL treatment caused expression changes of 303 proteins. As revealed by protein functional analysis, oxLDL uptake caused a multifaceted molecular response that involved numerous biological pathways. This response included up-regulation of anti-oxidative stress proteins whose expression is mediated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), confirming results of transcriptomics studies previously published by us and others. Significantly, and previously unreported, the oxLDL treatment induced down-regulation of ribosomal and translation initiation proteins, and up-regulation of proteins involved in autophagy, thus suggesting that a major cellular mechanism through which the RPE mitigate oxLDL-induced damage involves inhibition of protein synthesis and removal of misfolded proteins.