Against a background of considerable epidemiological and other evidence implicating omega-3 fatty acids in the prevention of age-related macular degeneration (AMD), the negative results of the Age-Related Disease Study 2 (AREDS2) were unexpected. The possibility that the design, setting, intake or subjects of AREDS2 may not have permitted the prophylactic potential of omega-3 to be adequately demonstrated is considered. Epidemiological studies had indicated potential preventative effects of omega-3, and an earlier randomised prospective study (NAT2) showed that patients who achieved high red blood cell membrane EPA/DHA (eicosapentaenoic acid/docosahexaenoic acid) levels were significantly protected against AMD compared with those with permanently low EPA/DHA levels. Various methodological differences between these studies are considered. NAT2 included a true placebo group, whereas control subjects in AREDS2 received a nutritional formula already found to be effective in AREDS1, but no placebo for DHA/EPA supplementation. Differences in the handling of non-compliant subjects and the formulation of the test formulations are considered. Given these considerations, and other lines of evidence from laboratory and clinical studies, closing the chapter on omega-3 in AMD prevention may be premature.