Is research on traumatic brain injury (TBI) repeating the failures seen in studies on neuroprotection in stroke? Recent failures of pivotal randomized clinical trials on neuroprotection in TBI resemble the costly setbacks experienced by stroke investigators that resulted in the cessation of interventional pharmacological trials and withdrawal of investment by the pharmaceutical industry. Many hypotheses have been advanced to explain these translational failures, such as methodological failures leading to false-positive results in animal studies or false-negative results in clinical trials or that animal models might not sufficiently recapitulate human TBI. To combat translational nihilism about the failures of these trials, we intend to provide a constructive analysis of what could be learned to improve translational prediction of future trials on neuroprotection in TBI.