Moyamoya phenomenon is a term used to describe extensive collateralization of the circle of Willis arteries associated with severe unilateral or bilateral internal carotid artery stenosis or occlusion in the presence of certain conditions. Down syndrome is among these conditions. A case is reported of a young girl with Down syndrome who presented with fluctuating right-sided weakness and facial droop found to have cerebral ischemia. Subsequent investigations disclosed characteristic "puff of smoke" patterns on angiographic studies consistent with moyamoya phenomenon. The patient was initially treated with aspirin and eventually underwent an encephalomyosynangiosis. This young patient with Down syndrome and moyamoya phenomenon serves as a reminder of the association between these two conditions.