Stroke outcome is determined by delayed neuronal cell death and edema formation. TWEAK, a cytokine of the TNF superfamily, and its membrane receptor Fn14 promote ischemia-induced neuronal apoptosis and leakage of the blood-brain barrier. Both TWEAK and Fn14 are upregulated in experimental stroke models. In this study, we investigated whether TWEAK and Fn14 are upregulated in stroke patients. We measured serum concentrations of TWEAK in stroke patients and matched control subjects by ELISA. Expression of Fn14 in the brain was evaluated by real-time RT-PCR and immunohistochemistry. TWEAK serum concentrations were elevated in stroke patients. In autopsy samples, we found elevated mRNA levels of the receptor Fn14 and a trend towards higher TWEAK mRNA levels. In the infarcted and peri-infarct tissue immunostaining for Fn14 was enhanced. These data show that the cytokine TWEAK and its membrane receptor Fn14 are upregulated in stroke and suggest that they contribute to stroke outcome.