Objective: To evaluate the relationship between plasma biomarkers of systemic inflammation and incident age-related macular degeneration (AMD) in persons with the AIDS. Design: Case–control study. Methods: Participants with incident intermediate-stage AMD ( N = 26) in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) and controls ( N = 60) without AMD. Cryopreserved baseline plasma specimens were assayed for biomarkers of inflammation, including high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, interferon-γ inducible protein (IP)-10, soluble CD14 (sCD14), soluble CD163 (sCD163), and intestinal fatty acid-binding protein (I-FABP). Results: After adjustment for age, sex, and race/ethnicity, baseline mean ± standard deviation (SD) log 10 (mg/ml) plasma levels of CRP (0.52 ± 0.60 vs. 0.20 ± 0.43; P = 0.01) and mean ± SD log 10 (pg/ml) plasma levels of sCD14 (6.31 ± 0.11 vs. 6.23 ± 0.14; P = 0.008) were significantly higher among cases (incident AMD) than among controls (no AMD). There was a suggestion that mean ± SD baseline log 10 (pg/ml) plasma IL-6 levels (0.24 ± 0.33 vs. 0.11 ± 0.29; P = 0.10) might be higher among cases than controls. In a separate analysis of 548 participants in LSOCA, elevated baseline levels of plasma inflammatory biomarkers were associated with a greater risk of mortality but not with an increased risk of incident cataract. Conclusion: These data suggest that systemic inflammatory biomarkers are associated with incident AMD but not incident cataract in persons with AIDS, and that systemic inflammation may play a role in the pathogenesis of AMD.