Objective: Tissue kallikrein (TK) cleaves kininogen to produce the potent bioactive compounds kinin and bradykinin, which lower blood pressure and protect the heart, kidneys, and blood vessels. Reduction in TK levels is associated with cardiovascular disease and diabetes in animal models. In this study, we investigated the association of TK levels with event-free survival over 5 years in Chinese first-ever stroke patients. Methods: We conducted a case control study with 1,268 stroke patients (941 cerebral infarction, 327 cerebral hemorrhage) and 1,210 controls. Plasma TK levels were measured with an enzyme-linked immunosorbent assay. We used logistic regression and Cox proportional hazards models to assess the relationship between TK levels and risk of first-time or recurrent stroke. Results: Plasma TK levels were significantly lower in stroke patients (0.163 +/- 0.064mg/l vs 0.252 +/- 0.093mg/l, p < 0.001), especially those with ischemic stroke. After adjustment for traditional risk factors, plasma TK levels were negatively associated with the risk of first-ever stroke (odds ratio [OR], 0.344; 95% confidence interval [CI], 0.30-0.389; p < 0.001) and stroke recurrence and positively associated with event-free survival during 5 years of follow-up (relative risk, 0.82; 95% CI, 0.74-0.90; p < 0.001). Compared with the first quartile of plasma TK levels, the ORs for first-ever stroke patients were as follows: second quartile, 0.77 (95% CI, 0.56-1.07); third quartile, 0.23 (95% CI, 0.17-0.32); fourth quartile, 0.04 (95% CI, 0.03-0.06). Interpretation: Lower plasma TK levels are independently associated with first-ever stroke and are an independent predictor of recurrence after an initial stroke. ANN NEUROL 2011;70:265-273