High-level plasma D-dimer suggests hypercoagulable states. There is a lack of correlation study of plasma D-dimer level and prognosis according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. The goal of this study is to explore the relationship between the plasma D-dimer level and the outcome of acute ischemic stroke patients among different stroke subtypes. We conducted a study of acute ischemic stroke patients admitted to the Department of Neurology in Second Hospital of Lanzhou University within 7 days of symptom onset. They were divided into different groups based on their subtypes according to TOAST criteria. In all the patients the plasma D-dimer levels were detected within 24 h of admission. Clinical neurological assessments were performed in line with National Institutes of Health Stroke Scale (NIHSS) once daily on the day of admission and on the 14th day. The outcome was evaluated by neurological improvement rate. Comparisons were made among the different subtypes based on the level of plasma D-dimer and the outcome. A total of 300 patients with acute ischemic stroke were included, 40 with cardioembolism; 47 with large-artery atherosclerosis; 143 with small-artery occlusion, 5 with other etiology stroke; and 65 with undetermined etiology stroke. The level of plasma D-dimer was negatively related to the outcome (r = −0.41; P = 0.013). Patients with cardioembolism had the highest level of plasma D-dimer and they suffered the most serious neurological deficit and the worst outcome among the five subtypes, the difference was statistically significant (F = 5.34; P = 0.012); while the lacunar stroke patients had the best outcome with the lowest level of D-dimer. High-level plasma D-dimer of acute period strongly indicates an unfavorable clinical outcome.