BackgroundFatigue and sleep problems are common after a traumatic brain injury (TBI) and are experienced as highly distressing symptoms, playing a significant role in the recovery trajectory, and they can drastically impact the quality of life and societal participation of the patient and their family and friends. However, the etiology and development of these symptoms are still uncertain.ObjectiveThe aim of this study is to examine the development of fatigue and sleep problems following moderate to severe TBI and to explore the changes in underlying biological (pain, brain damage), psychological (emotional state), and social (support family, participation) factors across time.MethodsThis study is a longitudinal multicenter observational cohort study with 4 measurement points (3, 6, 12, and 18 months postinjury) including subjective questionnaires and cognitive tasks, preceded by 7 nights of actigraphy combined with a sleep diary. Recruitment of 137 moderate to severe TBI patients presenting at emergency and neurology departments or rehabilitation centers across the Netherlands is anticipated. The evolution of fatigue and sleep problems following TBI and their association with possible underlying biological (pain, brain damage), psychological (emotional state), and social (support family, participation) factors will be examined. ResultsRecruitment of participants for this longitudinal cohort study started in October 2017, and the enrollment of participants is ongoing. The first results are expected at the end of 2020.ConclusionsTo the authors’ knowledge, this is the first study that examines the development of both post-TBI fatigue and sleep longitudinally within a biopsychosocial model in moderate to severe TBI using both subjective and objective measures. Identification of modifiable factors such as mood and psychosocial stressors may give direction to the development of interventions for fatigue and sleep problems post-TBI.Trial RegistrationNetherlands Trial Register NTR7162; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=7162 (Archived by WebCite at http://www.webcitation.org/6z3mvNLuy)International Registered Report Identifier (IRRID)RR1-10.2196/11295