Purpose: To investigate the relationship of growth in drusen size with genetic susceptibility and adherence to the alternate Mediterranean diet. Methods: Participants in this analysis had complete ocular, genetic, and dietary data with mean follow-up time of 10.2 years in the Age-Related Eye Disease database. Maximal drusen size was graded on an ordinal scale and two-step progression was determined. A genetic risk score using variants associated with advanced AMD and derived from a stepwise regression model yielded 11 variants in 8 genes. Adherence to the alternate Mediterranean diet was assessed using a nine-component score based on intake of vegetables, fruits, legumes, whole cereals, fish, meat, nuts, alcohol, and monounsaturated-to-saturated fatty acids ratio. Multivariate Cox proportional hazards models were used. Results: Among 3023 eligible eyes, 19% had drusen growth. In the stepwise selection, common and rare risk alleles for CFH Y402H, CFH rs1410996, CFH R1210C, C3 R102G, C3 K155Q, and ARMS2/HTRA1, as well as VEGF-A, TIMP3, NPLOC4, and HSPH1 variants were significantly associated with 2-step progression in drusen size, and the C2 E318D protective allele conferred decreased risk, adjusting for other covariates. A higher genetic risk score conferred a higher risk (hazard ratio per 1-unit increase, 2.68; 95% confidence interval, 2.23–3.23; P < 0.001), and a medium/high adherence to alternate Mediterranean diet score (4–9) tended to lower risk (hazard ratio, 0.83; 95% confidence interval, 0.68–0.99; P = 0.049), adjusting for all covariates. Conclusions: Genetic susceptibility was independently related to drusen growth. A Mediterranean-style diet with healthful nutrient-rich foods (fruits, vegetables, legumes and fish), may reduce enlargement of drusen, the hallmark of AMD.< Réduire