BACKGROUND: Cognitive impairment (CI) affects about 40-70% of multiple sclerosis (MS) patients. Brain MRI explains about 33-50% of the CI variance in MS. The cognitive reserve (CR) hypothesis has been postulated to identify other factors that can account for more variance in this outcome. The objective of this study was to explore the impact of CR on cognitive performance in MS patients.METHODS: A total of 526 MS outpatients were recruited (70.9% females, 41.7 ± 11.1 years old). CR was cross-sectionally assessed by the CR Index questionnaire (CRIq). Cognitive assessment was performed using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) tool to evaluate information processing speed, verbal memory and visuospatial memory. The role of CRIq in MS cognition was investigated by using multiple linear regression models to account for possible confounders.RESULTS: In total 202 (38.4%) patients were found with CI (i.e. failure in at least one of the three cognitive tests used based on normative data from 212 healthy controls). The CRIq score of CI patients was lower than that of non-CI patients (p < 0.001). CRIq score was significantly correlated with information processing speed (rho = 0.364, p < 0.001), verbal memory (rho = 0.237, p < 0.001) and visuospatial memory (rho = 0.331, p < 0.001), having adjusted for age and sex. CRIq was also significantly associated with disability (rho = -0.188, p < 0.001) and depressive symptoms (rho = -0.220, p < 0.001). Roughly, CRIq, disability and depressive symptoms significantly explained 12.2-23.7% of cognitive performance in MS. A significant interaction between CRIq and disability was also found for information processing speed.CONCLUSION: CR has a protective role in MS-related cognitive dysfunction. The differential effect of CR on distinct cognitive domains is supported. Interventions targeting CR to prevent cognitive impairment in MS patients are warranted by the study findings.