Age-related macular degeneration (AMD) is a slow, progressive disease with both genetic and environmental risk factors. Free radical-induced oxidation of docosahexaenoate (DHA)-containing lipids generates omega-(2-carboxyethyl)pyrrole (CEP) protein adducts that are more abundant in ocular tissues from AMD than normal human donors. To understand better the role of oxidative damage in AMD, we have synthesized CEP-modified proteins, produced anti-CEP antibodies, and initiated analysis of CEP immunoreactivity and autoantibodies in human plasma. A highly selective rabbit polyclonal anti-CEP antibody was raised that binds CEP 1000 times more strongly than carboxypropylpyrrole, a close structural analogue. The CEP adduct uniquely indicates oxidative modification from DHA derivatives because CEP protein modifications cannot arise from any other common polyunsaturated fatty acid. Immunocytochemistry localized CEP to photoreceptor rod outer segments and retinal pigment epithelium in mouse retina and demonstrated more intense CEP immunoreactivity in photoreceptors from a human AMD donor compared with healthy human retina. The mean level of anti-CEP immunoreactivity in AMD human plasma (n = 19 donors) was 1.5-fold higher (p = 0.004) than in age-matched controls (n = 19 donors). Sera from AMD patients demonstrated mean titers of anti-CEP autoantibody 2.3-fold higher than controls (p = 0.02). Of individuals (n = 13) exhibiting both antigen and autoantibody levels above the mean for non-AMD controls, 92% had AMD. These results suggest that together CEP immunoreactivity and autoantibody titer may have diagnostic utility in predicting AMD susceptibility.