Complement factor 3 (C3) has emerged as a primary therapeutic target in age-related macular degeneration (AMD) supported by genetic, histologic, and clinical trial evidence. Yet, the site(s) of action are unclear. The purpose of this study was to test the effect of C3 knockout on photoreceptors and retinal pigment epithelial cells (RPE) in the sodium iodate (NaIO(3)) model, which mirrors some features of AMD. C3(-/-) and WT mice, both on a C57Bl/6J background, were injected intraperitoneally with 25 mg/kg NaIO(3). Electroretinography and optical coherence tomography were performed 7 days later to assess retinal function and structure, respectively. Then, mice were euthanized for retinal immunohistochemistry, quantitative real-time PCR and enzyme-linked immunosorbent assays. NaIO(3) increased C3 protein levels in the neural retina but not RPE. WT but not C3(-/-) mice showed NaIO(3)-induced iC3b deposition on photoreceptor outer segments. C3(-/-) mice were partially protected against photoreceptor layer thinning. There was partial preservation of rod and cone function in the C3(-/-) group. Neither RPE structure nor function was protected. These results suggest outer segment opsonization contributes to photoreceptor death in this model, and that targeting C3 can protect photoreceptor structure and function when RPE cells are stressed.