Background and Purpose-Differences in risk factor profiles between lacunar and other ischemic stroke subtypes may provide evidence for a distinct lacunar arteriopathy, but existing studies have limitations. We overcame these by pooling individual data on 2875 patients with first-ever ischemic stroke from 5 collaborating prospective stroke registers that used similar, unbiased methods to define risk factors and classify stroke subtypes. Methods-We compared risk factors between lacunar and nonlacunar ischemic strokes, altering the comparison groups in sensitivity analyses, and incorporated these data into a meta-analysis of published studies. Results-Unadjusted and adjusted analyses gave similar results. We found a lower prevalence of cardioembolic source (adjusted odds ratio, 0.33; 95% CI, 0.24 to 0.46), ipsilateral carotid stenosis (odds ratio, 0.21; 95% CI, 0.14 to 0.30), and ischemic heart disease (odds ratio, 0.75; 95% CI, 0.58 to 0.97) in lacunar compared with nonlacunar patients but no difference for hypertension, diabetes, or any other risk factor studied. Results were robust to sensitivity analyses and largely confirmed in our meta-analysis. Conclusions-Hypertension and diabetes appear equally common in lacunar and nonlacunar ischemic stroke, but lacunar stroke is less likely to be caused by embolism from the heart or proximal arteries, and the lower prevalence of ischemic heart disease in lacunar stroke provides additional support for a nonatherosclerotic arteriopathy causing many lacunar ischemic strokes. Our findings have implications for how clinicians classify ischemic stroke subtypes and highlight the need for additional research into the specific causes of and treatments for lacunar stroke. Key Words: stroke Ⅲ lacunar Ⅲ risk factors Ⅲ stroke subtypes A bout one quarter of ischemic strokes are caused by lacunar infarcts 1 resulting from the occlusion or, perhaps, leakiness 2 of one of the small perforating arteries supplying the deep subcortical areas of the brain. The arterial pathology remains poorly understood, with proposed mechanisms including lipohyalinosis, arteriosclerosis, poor cerebral blood flow, vasospasm, or abnormal endothelial function. 3 Much of our current understanding is based on the clinicopathological studies of Miller Fisher et al in the 1960s and 1970s. Progress since then has been limited, but there is growing evidence to suggest that the lacunar arteriopathy may differ from the atherothromboembolic processes that lead to occlusion of large intracranial and extracranial arteries, causing most other ischemic strokes. [2][3][4] One indirect approach to better understanding the arterial pathology of lacunar ischemic stroke is to look for differences in the vascular risk factor profiles of lacunar versus nonlacunar ischemic stroke, which may reflect distinct underlying pathologies and causes. In a previous meta-analysis of published studies that used an unbiased method (independent of vascular risk factors) to classify ischemic stroke subtypes, we found no difference in the preva...