• PURPOSE: To investigate the expression of the complement regulatory proteins CD46, CD55, and CD59 on peripheral leukocytes in neovascular age-related macular degeneration (AMD). • DESIGN: Prospective, case-control study. • METHODS: Thirty-five unrelated patients with neovascular AMD and 30 control individuals were included in this case-control study. All participants were subjected to a structured interview and detailed imaging (autofluorescence, digital funduscopy, spectral-domain optical coherence tomography, and fluorescein and indocyanine green angiography in patients suspected of having neovascular AMD) was performed. Fresh ethylenediamine- tetraacetic acid blood was obtained and stained with monoclonal antibodies. Using flow cytometry, the percentage of CD14+ monocytes, CD45 + lymphocytes, and CD45+ granulocytes positive for CD46, CD55, and CD59 was determined in patients with neovascular AMD and was compared with that of controls. • RESULTS: We found that the expression of CD46 and CD59 was significantly lower on CD14+ monocytes in patients with neovascular AMD compared with controls (P = .0070). A significantly lower expression of CD46 on lymphocytes was observed in patients with fibrosis compared with patients without fibrosis (P = .010). • CONCLUSIONS: Our study suggests that neovascular AMD is associated with an inadequate regulation of the complement system, supporting current evidence on the role of complement dysregulation in the pathogenesis of AMD.