We demonstrate histologically sub-retinal drusenoid debris in three aged human eyes, two of them affected by age-related maculopathy. By postmortem fundus examination, the lesions were drusen-like, i.e., they were pale spots apparently at the level of the retinal pigment epithelium (RPE). Light and electron microscopy revealed aggregations of membranous debris, the principal constituent of soft drusen, in the sub-retinal space. Immunohistochemistry and confocal microscopy confirmed the presence of molecules typically associated with drusen (positive for unesterified cholesterol, apoE, complement factor H, and vitronectin) without evidence for molecules associated with photoreceptors (lectin-binding disaccharide bridges and opsins), Müller cells (glial fibrillary acid protein and cellular retinal binding protein, CRALPB), or RPE (CRALPB). The fact that a drusenoid material, sharing some markers with conventional drusen, can occur on opposite faces of the RPE, suggests deranged polarity of normally highly vectorial processes for basolateral secretion from RPE, and that overproduction of secreted materials and direction of secretion are independently specified processes. In the future, drusenoid sub-retinal debris might be more frequently revealed by emerging high-resolution imaging techniques.