In the Early Treatment Diabetic Retinopathy Study (ETDRS), a multicenter clinical trial sponsored by the National Eye Institute, one eye of each patient was assigned randomly to early photocoagulation and the other to deferral of photocoagulation (i.e., careful follow-up and initiation of photocoagulation only if high-risk proliferative retinopathy developed). This design allowed observation of the natural course of diabetic retinopathy in the initially untreated eye. Gradings of baseline stereoscopic fluorescein angiograms of these eyes were used to examine relationships of angiographic characteristics with each other, with retinopathy severity level and macular edema status graded from color photographs, and with risk of progression from nonproliferative to proliferative retinopathy during 1 to 5 years of follow-up. Fluorescein leakage (particularly diffuse), capillary loss and dilatation, and various arteriolar abnormalities were associated with retinopathy severity and with the likelihood of progression to proliferative retinopathy during follow-up. Severity of fluorescein leakage was strongly associated with macular edema.