Angiopoietin-2 has been reported to regulate the inflammation process, which is associated with recurrence of stroke. The purpose of this study was to test the hypothesis that plasma levels of angiopoietin-2 and variants of angiopoietin-2 will confer risk of stroke recurrence. The association of plasma angiopoietin-2 (determined by using ELISA) and the variants in angiopoietin-2 promoter with stroke recurrence was tested in 1735 patients with stroke of three subtypes, lacunar infarct (n = 475), atherothrombotic (n = 794) and hemorrhage (n = 466), for a period of following-up 4.5 years (mean), the association was evaluated by using Kaplan-Meier analysis and the Cox regression models. We found that angiopoietin-2 levels were associated with risk of stroke recurrence in lacunar infarct patients. Taking the lowest quartile as reference, the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for stroke recurrence was 1.48 (0.74-2.95) for the second quartile, 2.56 (1.35-4.86) for the third and 2.15 (1.11-4.17) for the fourth. Allele T of rs3739391 in angiopoietin-2 promoter was associated with elevated angiopoietin-2 levels and increased risk of stroke recurrence in patients with lacunar infarct with HR 1.67 (1.06-2.63) relative to the allele C, but neither in those with atherothrombotic nor in those with hemorrhagic stroke. Our results indicate that both angiopoietin-2 and allele T of rs3739391 might be the risk marker for stroke recurrence in the patients with lacunar infarction. These findings may help to improve future prevention or therapy strategies for stroke. Even some conventional risk factors have been identified responsible for stroke recurrence, but these factors could not fully explain all the recurrent stroke events. Our study opens a new page for the first time that angiopoietin/tie2 pathway has a potential role in lacunar stroke recurrence. Since several strategies are available for blocking or neutralizing plasma angiopoietin-2, especially eicosapentaenoic acid rich in sea food. Our finding obviously has its clinical implication if it was proved by large, prospective clinical studies. (C) 2010 Elsevier Inc. All rights reserved.