We have shown previously that complement factor H (CFH) and complement factor B (CFB) are constitutively expressed by retinal pigment epithelial cells and their production is regulated by inflammatory cytokines, suggesting that the alternative pathway (AP) of complement activation might play a role in retinal inflammation. In this study, we further investigated the role of the AP in retinal inflammation using experimental autoimmune uveoretinitis (EAU) as a model. Mice with EAU show increased levels of C3d deposition and CFB expression in the retina. Retinal inflammation was suppressed clinically and histologically by blocking AP-mediated complement activation with a complement receptor of the Ig superfamily fusion protein (CRIg-Fc). In line with reduced inflammation, C3d deposition and CFB expression were markedly decreased by CRIg-Fc treatment. Treatment with CRIg-Fc also led to reduced T-cell proliferation and IFN-γ, TNF-α, IL-17, and IL-6 cytokine production by T cells, and reduced nitric oxide production in BM-derived macrophages. Our results suggest that AP-mediated complement activation contributes significantly to retinal inflammation in EAU. CRIg-Fc suppressed retinal inflammation in EAU by blocking AP-mediated complement activation with probable direct effects on C3/C5 activation of macrophages, thus leading to reduced nitric oxide production by infiltrating CRIg(-) macrophages.