Providing long-term follow-up of the natural history of age-related macular degeneration (AMD) and associated risk factors will facilitate future epidemiologic studies and clinical trials. To describe 10-year progression rates to intermediate or advanced AMD. We observed the Age-Related Eye Disease Study (AREDS) participants for an additional 5 years after a randomized clinical trial of antioxidant vitamins and minerals was completed. Observation occurred at 11 clinical sites of medical retinal practices from academic institutions and community medical centers. Participants aged 55 to 80 years with no AMD or AMD of varying severity (n = 4757) were followed up in the AREDS trial for a median duration of 6.5 years. When the trial ended, 3549 of the 4203 surviving participants were followed for 5 additional years. Treatment with antioxidant vitamins and minerals. Development of varying stages of AMD and changes in visual acuity. The rates of progression to large drusen and advanced AMD (neovascular AMD or central geographic atrophy) were evaluated using annual fundus photographs assessed centrally. Best-corrected visual acuity was measured at annual study visits. The risk of progression to advanced AMD increased with increasing age (P = .01) and severity of drusen. Women (P = .005) and current smokers (P < .001) were at increased risk of neovascular AMD. In the oldest participants with the most severe AMD status at baseline, the risks of developing neovascular AMD and central geographic atrophy by 10 years were 48.1% and 26.0%, respectively. Similarly, rates of progression to large drusen increased with increasing severity of drusen at baseline, with 70.9% of participants with bilateral medium drusen progressing to large drusen and 13.8% to advanced AMD in 10 years. Median visual acuity at 10 years in eyes that had large drusen at baseline but never developed advanced AMD was 20/25; eyes that developed advanced AMD had a median visual acuity of 20/200. The natural history of AMD demonstrates relentless loss of vision in persons who developed advanced AMD. These progression data and the risk factor analyses may be helpful to investigators conducting research in clinic populations.