Background and Purpose— We aimed to determine the incidence of co-occurring cerebral ischemia, extent of cerebral small vessel disease, and vascular risk profile of patients with acute retinal ischemia. Methods— RETIS (Frequency of Acute Silent Brain Infarction and Systematic Evaluation of Stroke Risk in Retinal Ischemia) was a single-center, prospective, observational study comprising ophthalmologic examination, brain magnetic resonance imaging, and extensive diagnostic work-up of vascular risk factors and stroke cause. Silent brain infarctions were identified on diffusion-weighted imaging, leukoaraiosis was quantified on fluid-attenuated inversion recovery sequences, and carotid artery stenosis was assessed by carotid ultrasound. Results— Of 112 patients with retinal ischemia, 77 (68.8%) had retinal arterial occlusion, and 35 (31.3%) presented with amaurosis fugax. Silent brain infarctions were found in 17 (15.1%) patients. Internal carotid artery stenosis was present in 19 (17.0%) and severe leukoaraiosis in 29 (25.9%) patients. Atrial fibrillation was detected in 14 (12.5%) patients. Patients with silent brain infarctions had higher rates of internal carotid artery stenosis (35.3% versus 13.7%; P =0.029) than those without, whereas leukoaraiosis and vascular risk factors were comparable between groups. Internal carotid artery stenosis was the only significant predictor of silent brain infarctions in multivariate analysis (odds ratio, 4.27; 95% confidence interval, 1.06–17.23). Conclusions— Silent cerebral ischemia is present in about 1 in 7 patients with retinal ischemia. The high rate of symptomatic internal carotid artery stenosis suggests that large artery atherosclerosis plays a major role in the pathogenesis of acute retinal ischemia.