 Up to 10 of patients with neovascular AMD treated with ranibizumab respond poorly or worsen despite therapy. The reason for this lack of response is unclear. We have preliminary data that suggests abnormal autoimmune activity is apparent in these patients. Previous studies have shown evidence of retinal autoimmunity in AMD patients, but there is very little data describing any specific immunologic commonality that correlates with disease andor poor response. 8,9 Perhaps just as significantly there is little data regarding the immunologic activity of age-matched normals, making published data hard to evaluate especially in this age group in which autoimmunity is known to increase. 8,9 While there are many known retinal antigens in autoimmune retinal disease, the role of these antigens is not well established in AMD and not all the antigens have been identified. 24 Moreover, RPE-reactivities are only beginning to be understood in ocular disease. 25-27 We intend to address humoral responses in AMD by making a systematic comparison of the immunologic activity of ranibizumab responders, ranibizumab initial non-responders, and a comparable population of age-sex-race matched normal controls. Data suggests that 5 groups of patients are evident after 3 treatments with ranibizumab: 1 rapid responders, 2 delayed responders, 3 gradual responders, 4 acutenon-responders and 5 chronic non-responders. We hypothesize that non-responders and gradual responders may in fact be patients with complicating underlying autoimmune activity involving retinal and RPE antigens, which are exposed secondary to the breakdown of the blood-retinal barrier during CNV development. We will study this humoral response antibody production over the treatment period, as it likely is changing at different rates in the patients with different responses. In addition we will correlate underlying genetic phenotype in these patients. 