Background: Secondary hydrocephalus is a well-known complication of severe acquired brain injuries (sABIs) often diagnosed during inpatient rehabilitation. Currently, there is no gold standard for its detection. Therefore, we designed a novel clinical diagnostic protocol that integrates clinical, functional, biochemical and neuroradiological assessments to improve the accuracy of its diagnosis in patients with sABIs. Methods: This prospective cohort study will be conducted in a tertiary referral rehabilitation center in Italy. A historical cohort of patients will be compared with a prospective cohort undergoing the new clinical diagnostic protocol. Expected Results: The expected results include an increase in the proportion of diagnosed cases, a reduced incidence of clinical complications, an increase in the rehabilitative outcomes at discharge, a significant reduction in the length of hospital stay, and useful information about the diagnostic and prognostic value of the neuroradiological characteristics. Conclusion: We expect that this clinical diagnostic protocol will result in a more appropriate assessment and timely treatment of secondary hydrocephalus in patients with sABIs, with the ultimate goal of improving their prognosis. In addition, it could be adopted by other rehabilitation centers to improve hydrocephalus diagnosis and treatment, thereby reducing the length of hospital stay and accelerating recovery with benefits for both patients and hospitals.