Until now, erythropoietin (EPO) was thought to be produced exclusively in fetal liver and adult kidney and to regulate mammalian erythropoiesis. However, we recently showed that steady state levels of EPO mRNA could be induced up to 100-fold in primary mouse astrocytes cultured under hypoxic conditions, and also reported the presence of mRNA for EPO and its receptor in the brain of mouse, monkey and human. In extending these studies on humans we now show that immunoreactive EPO is present in ventricular cerebrospinal fluid (CSF) of 5 patients with traumatic brain injuries: EPO was found in 15 out of 15 CSF samples. There was no correlation between the serum EPO concentration and the concentration in the CSF. However, EPO concentrations in CSF correlated with the degree of blood-brain-barrier dysfunction. This suggests that EPO does not cross the intact blood-brain-barrier, implying that EPO is produced in the brain itself, most probably by astrocytes in an oxygen-dependent manner. In view that neuronal cells carry the EPO receptor, we propose that EPO acts in a paracrine fashion in the central nervous system and might function as a protective factor against hypoxia-induced damage of neurons.