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Traumatic brain injury (TBI) is a leading cause of death and disability in the modern society. Although primary prevention is the only strategy that can counteract the primary brain damage, numerous preclinical studies have been accumulated in order to find therapeutic strategies against the secondary damage. In this scenario erythropoietin (EPO) has been shown to be a promising candidate as neuroprotective agent. A recent clinical trial, however, has shown that EPO has not an overall effect on outcomes following TBI thus renewing old concerns. However, the results of a prespecified sensitivity analysis indicate that the effect of EPO on mortality remains still unclear. In the light of these observations, further investigations are needed to resolve doubts on EPO effectiveness in order to provide a more solid base for tailoring conclusive clinical trials.