This application proposes to study the efficacy of vitamin D3 and marine omega-3 fatty acid supplementation for prevention of age-related macular degeneration (AMD), the leading cause of blindness in the US. The study will leverage invaluable resources and data from the VITamin D and OmegA-3 TriaL (VITAL), a randomized, double-blind, placebo-controlled, 2x2 factorial trial designed to test vitamin D (vitamin D3 [cholecalciferol], 2000 IU/d) and marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1 g/d) supplements in the primary prevention of cancer and cardiovascular disease. The National Institutes of Health (1U01CA138962) is funding the main VITAL trial, which will study 20,000 men aged e60 y and women aged $ e65 y. Beginning in October 2010 and continuing throughout 2011, willing and eligible respondents to an $ invitational mailing will be enrolled in a 3-month run-in, and subsequently those who remain willing and eligible, and who report having taken at least two-thirds of study pills, will be randomly assigned to 1 of 4 treatment groups for 5 years: vitamin D3 (2000 IU/d) and fish oil (EPA+DHA, 1 g/d); vitamin D3 and fish oil placebo; vitamin D3 placebo and fish oil; and vitamin D3 placebo and fish oil placebo. At 1-year intervals, participants will receive a new supply of pills and a follow-up questionnaire on compliance, possible side effects, and incidence of endpoints. We propose to ascertain prevalent and incident AMD endpoints in the VITAL cohort in order to study the efficacy of vitamin D3 and fish oil in AMD prevention. The Primary Aims of this ancillary study are to test whether: 1) fish oil supplementation (EPA+DHA, 1g/d) reduces the incidence and progression of AMD and whether 2) vitamin D3 supplementation (2000 IU/d) reduces the incidence and progression of AMD. Secondary Aims will test for synergistic or antagonistic effects of vitamin D3 and fish oil, as well as interactions of vitamin D3 and fish oil with common AMD-associated genetic polymorphisms, and polymorphisms related to pathways involved in vitamin D3 or omega-3 fatty acid metabolic activity. This research is responsive to a program priority of the National Eye Institute's Strategic Plan to develop new treatments for AMD. We believe the timely start of the proposed AMD ancillary to the VITAL trial offers a unique but time-sensitive opportunity to obtain a reliable, efficient, and informative evaluation o the efficacy of two extremely promising preventive agents for AMD at a fraction of the cost of separate trials. Given our success with prior mail-based, large, simple trials and cohort studies, our experience with AMD, and our proposed methodology, we believe the trial will be able to provide either definitive positive or informative null results regarding the study hypotheses. PUBLIC HEALTH RELEVANCE: The purported health benefits of vitamin D and omega-3 fatty acids are receiving increasing attention in the medical literature and the popular press. However, definitive data on health benefits and risks of these agents are lacking. Findings from this large clinical trial will clarify the role of vitamin D and omega-3 fatty acid supplements in he prevention of AMD, the leading cause of blindness in US men and women.