PURPOSE: Chronic inflammation, immune dysregulation, and oxidative stress are major drivers of age-related macular degeneration (AMD) pathogenesis. Lipopolysaccharide (LPS) is a potent proinflammatory toxin originating from gut bacteria. We assessed the association of a blood biomarker of LPS exposure with incident AMD. METHODS: The Alienor Study is a prospective population-based study, including 963 residents of Bordeaux (France), aged 73 years or more at baseline. Esterified 3-hydroxy fatty acids (3-OH FAs) were measured from blood samples as a proxy of LPS burden. AMD was graded from color retinal photographs and spectral domain optical coherence tomography, performed every two years from 2006 to 2017. Cox proportional hazards models were used to estimate associations of between esterified 3-OH FAs, using 722 eyes at risk for incident early AMD and 981 eyes at risk for incident advanced AMD. RESULTS: Higher esterified 3-OH FAs were associated with incident early AMD after adjusting for age and gender (hazard ratio [HR] = 1.21 for 1 standard deviation [SD] increase; 95% confidence interval [CI], 1.01-1.45; P = 0.04) but not with incident advanced AMD (HR = 1.03 for 1 SD increase; 95% CI, 0.73-1.45; P = 0.86). These associations remained stable after multivariate adjustment and imputation for missing covariates (early AMD HR = 1.22 for 1 SD increase; 95% CI, 1.01-1.46; P = 0.04; advanced AMD HR = 0.98 for 1 SD increase; 95% CI, 0.69-1.38; P = 0.91). CONCLUSIONS: This study evidenced an association between higher esterified 3-OH FAs and incident early AMD, suggesting that exposure to LPS may be involved in the early pathophysiological processes of AMD.