The relationship of retinal microaneurysms to the progression of diabetic retinopathy over a 4-year period was examined in a population-based sample of diabetic persons. The number of microaneurysms in color stereoscopic fundus photographs of seven standard fields was counted in the eyes of diabetic persons (n = 236) who had only microaneurysms in photographs at the baseline examination. If only one eye was involved (n = 121), the mean number of microaneurysms was 2.3; with bilateral involvement (n = 115), the mean was 9.3 in the more involved eye. The number of microaneurysms at the baseline examination was positively associated with significant progression of retinopathy. This relationship remained after controlling for the level of glycosylated hemoglobin. These data suggest that the number of microaneurysms at baseline is an important predictor of progression of diabetic retinopathy. Microaneurysm counts may prove to be a useful early end point in clinical trials.