Purpose To determine the prevalence of reticular pseudodrusen (RPD) and its association with age-related macular degeneration (AMD) and AMD risk factors in a large sample. Design Community-based cohort study in Melbourne, Victoria, Australia. Participants A total of 21130 participants 48 to 86 years of age available for ophthalmic assessment at follow-up from 2003 through 2007. Methods Lifestyle, diet, and anthropometric measurements were obtained at baseline and follow-up. At follow-up, digital macular color photographs were graded for early, intermediate, and late AMD as well as the presence of RPD. Data were analyzed using multinomial logistic regression controlling for age, gender, smoking, country of birth, and diet. Main Outcome Measures Detection of RPD based on color fundus photographs. Results Prevalence of RPD was 0.41% (87 of 21130 participants), with 51% having bilateral RPD. Patients with RPD were older compared with patients with large drusen (>125 μm; 76±4 vs. 68±9 years; P < 0.001). Increasing age, female gender, being a current smoker, as well as focal pigmentary abnormalities and large drusen (>125 μm) were associated with a higher prevalence of RPD. Presence of geographic atrophy (GA) was associated with the highest odds of having RPD (odds ratio [OR], 153; 95% confidence interval [CI], 53-442), followed by choroidal neovascularization (CNV; OR, 90; 95% CI, 26-310), intermediate AMD (OR, 33; 95% CI, 14-77), and early AMD (OR, 12; 95% CI, 5-31) compared with those with no AMD. The ARMS2 single nucleotide polymorphism (SNP) rs10490924, HTRA1 SNPs rs11200638 and rs3793917, and CFH SNPs rs393955, rs1061170, and rs2274700 were associated with increased prevalence of RPD (all P < 0.05). Conclusions Reticular pseudodrusen are highly concurrent with AMD and have similar associations with known AMD risk factors such as age, gender, smoking, and genetic risk factors. Reticular pseudodrusen are associated more strongly with GA than with CNV. Although RPD are not specific to AMD they are likely to be a strong risk factor for progression to late-stage AMD similar to focal pigmentary abnormalities and large drusen.