Prognostic studies of mild traumatic brain injury (MTBI) can serve many purposes. First, they are used to describe paths and outcomes of patients with MTBI. Second, they provide information on which characteristics are associated with the occurrence of outcomes. Third, they provide insight into the causation of poor or favorable course of the disease. Finally, they can assess how differences in the probability of outcomes can help predict the course of patients. In this article, we summarize methodologic principles used by the International Collaboration on MTBI Prognosis to appraise the prognostic literature. Differentiating prognostic factors (causally linked with outcome), prognostic markers (associated but not causally), and predictors is important to guide interventions, public health policy, and research. Ideally, prognostic studies need a clear statement of the type of question (hypothesis-generating descriptive, exploration of possible prognostic variables, confirmatory modeling of prognosis); a cohort study design with standardized follow-up of a representative population of patients with MTBI; a standardized data collection using reliable and accurate tools to capture clinically, biologically, psychologically, or socially relevant variables and outcomes; and an analysis of data based on survival methods. Interpretation of prognostic studies should consider biases related to differential inclusion of nonrepresentative samples of patients, poor measurements of outcomes, and poor control for confounders. Transferring prognostic results into clinical practice should be based on estimates of the predictive performance of models and on a demonstration that patient outcomes can be improved by the use of prediction rules.