A secreted isoform of the receptor for advanced glycation end products (RAGE), soluble RAGE (sRAGE), can neutralize the adverse effects of RAGE signaling by acting as a decoy. RAGE signaling contributes to the development of diabetic microangiopathy, however few studies have addressed pivotal roles of RAGE signaling in acute stroke. We examined plasma sRAGE levels associated with clinical features in acute stroke patients. Plasma sRAGE was measured in 482 patients (318 men; mean age 71 years) admitted within three days of stroke onset. Median values of sRAGE were significantly different among stroke subtypes (p=0.001); 1010 pg/ml in atherothrombotic infarction, 933 pg/ml in lacunar, 1280pg/ml in cardioembolic infarction, 1050 pg/ml in other types of infarctions, and 943 pg/ml in primary intracerebral hemorrhage. Severe leukoaraiosis on brain MR images, high NIHSS scores on admission, cigarette smoking, and normal estimated glomerular filtration rate were significantly associated with low sRAGE levels (p<0.05). The low level of sRAGE was associated with severe leukoaraiosis, reflecting long-standing presence of hypertensive angiopathy. Kidneys play a role in the removal of sRAGE. RAGE signaling can contribute to the deterioration of neuronal damage under severe leukoaraiosis, result in a high NIHSS score on admission in acute stroke patients, especially those with smoking habits.