During the National Neurotrauma Symposium 2010, the DG Research of the European Commission and the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) organized a workshop on comparative effectiveness research (CER) in traumatic brain injury (TBI). This workshop reviewed existing approaches to improve outcomes of TBI patients. It had two main outcomes: First, it initiated a process of re-orientation of clinical research in TBI. Second, it provided ideas for a potential collaboration between the European Commission and the NIH/NINDS to stimulate research in TBI. Advances in provision of care for TBI patients have resulted from observational studies, guideline development, and meta-analyses of individual patient data. In contrast, randomized controlled trials have not led to any identifiable major advances. Rigorous protocols and tightly selected populations constrain generalizability. The workshop addressed additional research approaches, summarized the greatest unmet needs, and highlighted priorities for future research. The collection of high-quality clinical databases, associated with systems biology and CER, offers substantial opportunities. Systems biology aims to identify multiple factors contributing to a disease and addresses complex interactions. Effectiveness research aims to measure benefits and risks of systems of care and interventions in ordinary settings and broader populations. These approaches have great potential for TBI research. Although not new, they still need to be introduced to and accepted by TBI researchers as instruments for clinical research. As with therapeutic targets in individual patient management, so it is with research tools: one size does not fit all.