Comparative effectiveness research (CER) is emerging as a commonly applied technique to determine the usefulness of medical interventions. Such research aims to compare various treatments for specific disease entities for overall effectiveness and potential for harm. According to the Centers for Disease Control, an estimated 1.7 million patients sustain a traumatic brain injury (TBI) annually in the US. In this review the authors examine the existence of CER reports in the area of neurotrauma to date and consider the context in which clinical research and evidence-based guidelines have and will continue to inform such analyses, with special attention to TBI.