Objective: The objective of this study was to assess the prognostic value of interarm difference of blood pressure (IAD) measured in acute ischemic stroke and to investigate its association with systemic atherosclerosis. Methods: This was a hospital-based retrospective observational study. Survival data and systolic/diastolic IAD were collected in patients with acute ischemic stroke. Systemic atherosclerosis was determined based on coronary CT angiography, transesophageal echocardiography, ankle-brachial index examination, and cerebral angiography covering both intracranial and extracranial cerebral arteries. Results: Of 834 patients, 10.3% had a systolic IAD ≥10 mm Hg, and 6.0% had a diastolic IAD ≥10 mm Hg. During a mean follow-up period of 2.96 6 0.95 years, 92 patients died (including 68 cardiovascular deaths). In multivariate Cox regression adjusted for cardiovascular risk factors and initial stroke severity, the presence of systolic IAD ≥10 mm Hg was associated with increased risk of allcause mortality (hazard ratio [HR] 1.97, 95% confidence interval [CI] 1.16-3.35) and cardiovascular mortality (HR 2.49, 95% CI 1.39-4.46). Patients with diastolic IAD ≥10 mm Hg also had increased risk of all-cause mortality (HR 3.43, 95% CI 1.94-6.08) and cardiovascular mortality (HR 3.51, 95% CI 1.83-6.74). The presence of systolic or diastolic IAD ≥10 mm Hg was associated with peripheral artery disease in the lower limbs, but not with atherosclerosis in the cerebral artery, coronary artery, or the aorta. Conclusions: The presence of interarm systolic or diastolic blood pressure difference $10 mm Hg is a strong independent prognostic marker in acute ischemic stroke.