PURPOSE: Due to the slowly progressing nature of age-related macular degeneration (AMD) and critical differences in ocular anatomy between humans and animals, it has been difficult to model disease progression, hampering the development of novel therapeutics aimed at impacting drusen biogenesis. To determine whether "drusen-in-a-dish" model systems are of utility in screening potential therapeutics aimed at early-intermediate dry AMD, we developed a detailed characterization of the protein, glycoprotein, and lipid composition of sub-retinal pigment epithelium (RPE) deposits grown by monolayers of ex vivo porcine RPE with human drusen in AMD globes. METHODS: Immunohistochemistry and imaging mass spectrometry (IMS) were performed on 20-week aged monolayers of porcine RPE and human donor globes recovered from an 81-year-old non-transplant donor with confirmed diagnosis of bilateral dry AMD. The presence of major protein, glycoprotein, and lipid species was compared between porcine sub-RPE deposits and human drusen with reference to macular/peripheral eccentricity. RESULTS: The protein and glycoprotein composition of porcine sub-RPE deposits closely mimics human drusen identified in donor globes with dry AMD, including the presence of major complement components (C9, CFH, CHI), apolipoproteins (ApoE, ApoJ), extracellular matrix proteins (vitronectin, collagen VI), and calcification (hydroxyapatite). Sub-RPE deposits were additionally rich in long-chain ceramide species (Cer, CerPE, PI), which have only recently been described in human drusen. CONCLUSIONS: Due to their compositional similarity to human drusen, ex vivo "drusen-in-a-dish" systems represent a potentially robust and cost-effective model for both studying the pathobiology of drusen biogenesis and screening novel therapeutics aimed at limiting drusen formation.