BACKGROUND: The association between lutein/zeaxanthin intake and age-related macular degeneration (AMD) risk may differ by smoking status, vitamin C and E intakes, and body fatness. OBJECTIVE: The objective was to evaluate the association between lutein/zeaxanthin intake and AMD risk by smoking status, intake of antioxidant vitamins, and body fatness. DESIGN: We conducted a prospective follow-up study of 71 494 women and 41 564 men aged >or=50 y and had no diagnosis of AMD or cancer. Diet was assessed with a validated semiquantitative food-frequency questionnaire. RESULTS: During up to 18 y of follow-up, we documented 673 incident cases of early AMD and 442 incident cases of neovascular AMD with a visual loss of 20/30 or worse due primarily to AMD. Lutein/zeaxanthin intake was not associated with the risk of self-reported early AMD. There was a statistically nonsignificant and nonlinear inverse association between lutein/zeaxanthin intake and neovascular AMD risk; the pooled multivariate relative risks for increasing quintiles of intake were 1.00 (referent), 0.80, 0.84, 0.97, and 0.72 (95% CI: 0.53, 0.99) (P for trend = 0.14). For early AMD, the association with lutein/zeaxanthin intake did not vary by smoking status, intakes of vitamins C and E, or body mass index. For neovascular AMD, a nonlinear inverse association was found among never smokers. CONCLUSIONS: These data do not support a protective role of lutein/zeaxanthin intake on risk of self-reported early AMD. The suggestion of inverse associations related to the risk of neovascular AMD needs to be examined further.