Background: Intracranial large artery stenosis (ILAS) is an important contributor to ischemic stroke in the United States and worldwide. There is evidence to suggest that chronic exposure to certain infectious agents may also be associated with ILAS. We aimed to study this association further in an ethnically diverse, prospective, population-based sample of Northern Manhattan. Methods: We enrolled a random sample of stroke-free participants from an urban, racially, and ethnically diverse community in 1993. Participants have been followed prospectively and a subset underwent brain magnetic resonance angiograms from 2003 to 2008. Intracranial stenoses of the circle of Willis and vertebrobasilar arteries were scored as 0=no stenosis, 1≤50% (or luminal irregularities), 2=50% to 69%, 3≥70% stenosis, and 4=flow gap. We summed the individual score of each artery to produce a global ILAS score (possible range, 0–44). Past infectious exposure to Chlamydia pneumoniae , Helicobacter pylori , cytomegalovirus, and herpes simplex virus 1 and 2 was determined using serum antibody titers. Results: Among 572 NOMAS (Northern Manhattan Study) participants (mean age 71.0±8.0 years, 60% women, 68% Hispanic) with available magnetic resonance angiogram and serological data, herpes simplex virus 2 (beta=0.051, P <0.001) and cytomegalovirus (beta=0.071, P <0.05) were associated with ILAS score after adjusting for demographics and vascular risk factors. Stratifying by anterior and posterior circulations, herpes simplex virus 2 remained associated with the anterior circulation (beta=0.055 P <0.01) but not with posterior circulation ILAS score. Conclusions: Chronic infectious exposures, specifically herpes simplex virus 2 and cytomegalovirus were associated with asymptomatic ILAS as seen on magnetic resonance angiogram imaging. This may represent an additional target of intervention in the ongoing effort to stem the substantial global burden of strokes related to ILAS.