Atherosclerosis plays an important role in ischemic stroke. We conducted this prospective study to determine significant factors related to progression of middle cerebral artery (MCA) stenosis. We studied 103 patients with MCA stenosis using transcranial Doppler (TCD) and re-evaluated the TCD results at 6 months after the initial investigation and measured platelet aggregability for adenosine diphosphate (ADP) or arachidonic acid (AA). After 6 months, 13 (12.6%) patients showed worsening, whereas 90 were stationary or showed regression upon TCD examination. In a univariate analysis, the history of ischemic stroke (P = 0.023), the presence of significant carotid stenosis (P = 0.027), the prescription of aspirin only (P = 0.046), the grade of stenosis in the MRA (P = 0.0048), and the platelet aggregability for ADP (P = 0.015) were significantly associated with the progression of MCA stenosis. After multiple logistic regression analysis, the grades of stenosis and platelet aggregability for ADP were independent factors related to the progression of MCA stenosis. In this study, the grade of MCA stenosis on angiography might be an important factor to predict the progression upon serial TCD examination. Also, the extent of inhibition of platelet activation could be a possible role to determine on the progression of MCA stenosis.