Objective: To describe the relationship of systemic inflammatory disease, complement factor H (CFH) Y402H (1277T→C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese. Design: Population-based, cross-sectional study. Participants: We included 5887 persons aged 45 to 84 years with gradable AMD. Methods: Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of antiinflammatory agents obtained. Main Outcome Measure: Prevalence of AMD. Results: While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [ln] units, 2.34; 95% confidence interval [CI], 1.33-4.13) and interleukin-6 (OR per SD in ln, 2.06; 95% CI, 1.21-3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14-2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06-1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14-3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00-3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10-2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09-3.10), and large drusen area (OR, 1.66; 95% CI, 1.02-2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks. Conclusions: This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.