Leukoaraiosis (LA) has been associated with abnormalities of both large and small blood vessels. This study attempts to clarify the pathogenesis of LA by testing the hypothesis that increased frequency of LA with occlusive extra-cranial arterial disease results directly from global reduction in cerebral blood flow (CBF). Thirty-five normal subjects and 55 patients with carotid stenosis (>70%) were studied using MR. CBF was measured using phase contrast MR angiography and LA was scored using previously validated scoring system. Patients were divided into those with evidence of previous infarction on MRI and those without. LA was more severe in patients than in normal subjects (P<0.01) and correlated with age in normal subjects but not in patients. CBF in patients with (809+/-214 ml/min) and without infarction (mean 792+/-181 ml/min) was significantly lower than in normal subjects (mean 1073+/-194 ml/min). There was no correlation between the severity of LA and measured CBF in any group. The severity of LA is greater in patients with severe carotid stenosis but is not correlated to reductions in CBF. This suggests that microvascular abnormality is the dominant pathogenetic factor in LA even in the presence of severe stenotic/occlusive large vessel disease.