Purpose To describe the microscopic structure of photoreceptors impacted by subretinal drusenoid deposits, also called pseudodrusen, an extracellular lesion associated with age-related macular degeneration (AMD), using adaptive optics scanning laser ophthalmoscopy (AOSLO). Design Observational case series. Methods We recruited 53 patients with AMD and 10 age-similar subjects who had normal retinal health. All subjects underwent color fundus photography, infrared reflectance, red-free reflectance, autofluorescence, and spectral-domain optical coherence tomography (OCT). Subretinal drusenoid deposits were classified by a 3-stage OCT-based grading system. Lesions and surrounding photoreceptors were examined by AOSLO. Results Subretinal drusenoid deposits were found in 26 eyes of 13 patients with AMD and imaged by AOSLO and spectral-domain OCT in 18 eyes (n = 342 lesions). Spectral-domain OCT showed subretinal drusenoid deposits as highly reflective material accumulated internal to the retinal pigment epithelium. AOSLO revealed that photoreceptor reflectivity was qualitatively reduced by stage 1 subretinal drusenoid deposits and was greatly reduced by stage 2. AOSLO presented a distinct structure in stage 3, a hyporeflective annulus consisting of deflected, degenerated or absent photoreceptors. A central core with a reflectivity superficially resembling photoreceptors is formed by the lesion material itself. A hyporeflective gap in the photoreceptor ellipsoid zone on either side of this core shown in spectral-domain OCT corresponded to the hyporeflective annulus seen by AOSLO. Conclusions AOSLO and multimodal imaging of subretinal drusenoid deposits indicate solid, space-filling lesions in the subretinal space. Associated retinal reflectivity changes are related to lesion stages and are consistent with perturbations to photoreceptors, as suggested by histology. © 2014 by Elsevier Inc. All rights reserved.