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Abstract Background Neuropsychological symptoms in the Cognitive, Energetic, Behavioural, and Affective (CEBA) domains are common in people with multiple sclerosis (PwMS) and can negatively affect societal participation. The current study aims to investigate whether there are combinations of symptoms in the different CEBA domains that consistently occur together, that is, if there are CEBA profiles that can be identified. If so, this study aims to develop a screening instrument identifying CEBA profiles in PwMS to select the most suitable neuropsychological rehabilitation treatment for a given CEBA profile and consequently improve the societal participation of PwMS. Methods This study is an observational, prospective cohort study consisting of 3 phases. Phase 1 focuses on the identification of CEBA profiles in a large sample of PwMS (n = 300). Phase 2 focuses on validating these CEBA profiles through replication of results in a new sample (n = 100) and on the development of the screening instrument. Phase 3 focuses on qualitatively evaluating in a small group of PwMS whether the selected treatment is suitable for the given CEBA profile or whether existing neuropsychological treatments should be adapted to meet the needs of PwMS suffering from symptoms in multiple CEBA domains simultaneously. Primary outcome is the CEBA profile, which will be derived from performance on neuropsychological assessment consisting of tests and questionnaires regarding the CEBA domains using a latent profile analysis. Inclusion criteria include MS diagnosis, sufficient ability in the Dutch language, and an age between 18 and 70 years. Discussion The results of the current study will contribute to a more comprehensive understanding of the entire spectrum of neuropsychological symptoms in PwMS. Identification of possible CEBA profiles, and accordingly, the development of a screening instrument determining the CEBA profile of PwMS in clinical practice, contributes to the timely referral of PwMS to the most suitable neuropsychological rehabilitation treatment. If necessary, adjustments to existing treatments will be suggested in order to sufficiently meet the needs of PwMS. All of this with the ultimate aim to improve societal participation, and thereby quality of life, of PwMS. Trial registration Dutch Central Committee on Research Involving Human Subjects (CCMO) NL83954.042.23; ClinicalTrials.gov NCT06016309.