Purpose: To examine the association between age-related changes in the T-cell compartment and prevalence of age-related macular degeneration (AMD). Design: Case-control study. Participants: A total of 117 AMD cases and 106 controls were included prospectively. Methods: Fresh-drawn peripheral blood samples were processed for flow cytometric analysis of T-cell populations. Plasma samples were analyzed for anti-cytomegalovirus (CMV) immunoglobulin (Ig)G and complement factor H (CFH) Y402H genotype. The diagnosis of AMD was made according to the Clinical Age-Related Maculopathy Staging System. Main Outcome Measures: Association between frequency of aged T cells and prevalence of AMD. Results: The prevalence of AMD was associated with distinct age-related changes in the T-cell compartment. Specifically, the patients with AMD had an increased frequency of CD28- T cells that expressed the CD56 surface marker (patients, 34.9% vs. aged controls, 25.8%; P = 0.002). Participants in the highest tertile of CD56+ CD28- T cells had an odds ratio (OR) for the presence of AMD of 3.2 (95% confidence interval [CI], 1.2-8.8) after adjustment for CFH genotype, anti-CMV IgG positivity, age, sex, and smoking history. The adjusted OR of the presence of AMD for persons having at least 1 CFH H402 risk allele increased from 3.5 (95% CI, 1.5-8.1) to 13.3 (95% CI, 3.3-53.6) for persons with at least 1 CFH H402 risk allele and above the median level of CD56+ CD28- T cells. Conclusions: We found increased levels of circulating aged CD56+ CD28- T cells in patients with AMD. Although this supports the notion of AMD as a systemic disease, it also suggests that the adaptive immune system is implicated in its pathogenesis. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.