© 2019 American Academy of Ophthalmology Purpose: To describe the progression and regression of individual subretinal drusenoid deposits (SDDs) and surrounding photoreceptors and retina in patients with age-related macular degeneration (AMD) over a 3.5-year period using multimodal imaging including adaptive optics scanning laser ophthalmoscopy (AOSLO). Design: Longitudinal observational study. Participants: Four patients with intermediate AMD. Methods: Six eyes of 4 patients with intermediate AMD each were imaged 4 times over 3.5 years. Five eyes of 3 patients showed only SDD and no drusen. Subretinal drusenoid deposit presence and progression were assessed by multimodal imaging and a 3-stage grading system based on spectral-domain (SD) OCT. Morphologic features and the fine structure of individual SDD lesions identified at baseline were examined by AOSLO at follow-up visits. Reflectivity of photoreceptors surrounding SDD were assessed with AOSLO and SD OCT. Main Outcome Measures: Morphologic features, fine structure, and size of individual SDD lesions by AOSLO; photoreceptor integrity surrounding SDD via AOSLO and SD OCT; and retinal layer thicknesses via SD OCT. Results: Individual SDDs followed independent lifecycle trajectories, exhibiting growth, shrinkage, fusion, and disappearance. Alterations in shape, morphologic features, and internal structure were not obviously the result of the presence of invading phagocytes. Of 822 lesions across all stages examined at baseline, 566 (69%) grew, 123 (15%) shrank, 47 (6%) remained of similar size, 86 (11%) disappeared, and 5 (0.6%) reappeared after regression. A return of characteristic photoreceptor reflectivity in AOSLO (punctate) and in SD OCT (prominent ellipsoid zone) was observed after regression of some SDD in 5 eyes of 4 patients. All eyes exhibited thinning of photoreceptor layers, despite intact retinal pigment epithelium (RPE), to approximately 70% of baseline thicknesses, as well as poorly visible or undetectable outer retinal bands. Conclusions: Adaptive optics scanning laser ophthalmoscopy and SD OCT imaging of individual SDDs over 3.5 years revealed independent trajectories of progression and regression, believed to reflect the activities of local outer retinal cells. Restoration of some photoreceptor reflectivity and intact RPE after SDD regression should be seen in the larger context of outer retinal atrophy, previously suggested as a new form of advanced AMD, and herein replicated.