A series of 24 consecutive patients presenting with a fundus picture characterized by a predominance of cotton-wool spots, or a single cotton-wool spot, is reported. Excluded were patients with known diabetes mellitus. Etiologic conditions found included previously undiagnosed diabetes mellitus in five patients, systemic hypertension in five patients, cardiac valvular disease in two patients, radiation retinopathy in two patients, and severe carotid artery obstruction in two patients. Dermatomyositis, systemic lupus erythematosus, polyarteritis nodosa, leukemia, AIDS, Purtscher's retinopathy, metastatic carcinoma, intravenous drug abuse, partial central retinal artery obstruction, and giant cell arteritis were each found in one patient. In only one patient did a systemic workup fail to reveal an underlying cause. The presence of even one cotton-wool spot in an otherwise normal fundus necessitates an investigation to ascertain systemic etiologic factors.