Copyright © by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited. Purpose: To evaluate eyes with refractile drusen using clinical imaging and to identify candidate histologic correlates of refractile drusen. Methods: Refractile drusen were defined as drusenoid material containing small refractile spherules. Retrospective analysis of color, autofluorescence, and spectral domain optical coherence tomography images of eyes with refractile drusen was performed to characterize the morphology and topography of these lesions. Macular sections from donor eyes were processed with a von Kossa stain for calcium phosphate and viewed by light microscopy. Punches of retinal pigment epithelium-choroid from donors with geographic atrophy were prepared for transmission electron microscopy. Results: Fundus findings of 14 eyes of 10 patients with age-related macular degeneration (age, 82.9 ± 5.6 years) were evaluated. A generalized loss of autofluorescence signal over refractile drusen appeared to spread over a larger area than each druse, for drusen located centrally. By color fundus photography, refractile drusen showed corresponding depigmentation around drusen that were located in the center of the macula. Optical coherence tomography imaging of refractile drusen showed hyperreflective dots. In the histologic specimens, drusen contained many small spherules rich in calcium phosphate. Ultrastructural examination of the spherules showed complex assemblies consisting of concentric shells containing thin layers of calcium. Conclusion: Refractile drusen appear to be a stage of drusen regression marked by loss of retinal pigment epithelium, thus contributing to the development of geographic atrophy. Calcium-containing spherules appear to account for the glistening appearance.