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Objective: To test the hypothesis that digoxin, an inhibitor of Na(+)-K(+)-ATPase activity, accelerates the progression of diabetic retinopathy., Research Design and Methods: We compared the incidence and risk of retinopathy in 120 digoxin-taking vs. 867 non-digoxin-taking diabetic participants in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) and in 117 digoxin-taking vs. 1,883 non-digoxin-taking diabetic subjects in the Early Treatment Diabetic Retinopathy Study (ETDRS). In both studies, retinopathy was detected by grading stereoscopic color photographs using the modified Airlie House classification scheme, and a two-step difference in baseline retinopathy grade was considered significant., Results: After controlling for other risk factors, we found no statistically significant association with either 4-year incidence of retinopathy (WESDR) or progression of retinopathy (WESDR and ETDRS) in patients taking digoxin at baseline compared with those not taking digoxin., Conclusions: These data suggest that digoxin therapy does not adversely affect the course of diabetic retinopathy.