Background and Purpose— Small-vessel disease contributes to the pathophysiology of stroke, and retinal microvascular signs have been linked to the risk of stroke. We examined the relationship of retinal signs with incident stroke in a multiethnic cohort. Methods— The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study that enrolled participants without clinical cardiovascular diseases from 6 US communities between 2000 and 2002. Of the participants, 4849 (71.2%) had fundus photography performed in 2002 to 2004. Retinopathy and retinal vessel caliber were assessed from retinal images. Stroke risk factors including high-sensitivity C-reactive protein, carotid artery intima-media thickness, and coronary artery calcium were measured using standardized protocols. Incident stroke was confirmed from medical record review and death certificates. Results— After 6 years of follow-up, there were 62 incident strokes. Narrower retinal arteriolar caliber was associated with increased risk of stroke after adjusting for conventional cardiovascular risk factors (adjusted incidence rate ratio, 2.83; 95% CI, 1.34—5.95; P =0.006; adjusted hazard ratio, 3.01; 95% CI, 1.29–6.99; P =0.011). Retinopathy in persons without diabetes was associated with increased risk of stroke (adjusted adjusted incidence rate ratio, 2.96; 95% CI, 1.50–5.84; P =0.002; adjusted hazard ratio, 3.07; 95% CI, 1.17–8.09; P =0.023). These associations remained significant after adjusting for high-sensitivity C-reactive protein, carotid intima-media thickness, or coronary artery calcium. Conclusions— Narrower retinal arteriolar caliber and retinopathy in nondiabetic persons were associated with increased risk of stroke in this relatively healthy multiethnic cohort independent of traditional risk factors and measures of atherosclerosis. The association between narrower retinal arteriolar caliber and stroke warrants further investigation.