The aim of this study was to value of TWEAK protein in stroke diagnosis and the correlation between Tweak level and lesion size on diffusion MRI in patients admitted to emergency department for acute stroke. Our study was prospectively conducted in a group of patients diagnosed with stroke in the emergency department and a control group between 1 June 2014 and 31 August 2014. Age, sex, vital parameters, comorbid conditions, neurological deficit level, Tweak level, and involved volume on D-MRI were analyzed. Age, sex, vital parameters, comorbid conditions, and Tweak levels were compared between the patient and control groups. Tweak level was compared with neurological deficit and diffusion on D-MRI imaging in the patient group. The results were evaluated in a confidence interval of 95% and at a significance level of p<0.05. There were no significant differences between both groups with respect to age and sex distribution. The median Tweak level of the patient group was significantly higher (912.1 pg/ml vs 808.3 pg/ml, p<0.05). In the patient group NIHSS score had a positive correlation to MRI lesion size (p<0.05) but not to Tweak level (p>0.05). There was no correlation between Tweak level and the involved area on diffusion MRI (p>0.05).In conclusion, Tweak appears as a parameter that can be used in patients with a clinical presentation consistent with Stroke. It can be used for diagnostic purposes when cranial CT does not support the diagnosis or for supporting diagnosis when D-MRI is not available.