BACKGROUND: Cognitive impairment (CI) is detected in 40-70% of multiple sclerosis (MS) patients, but only 33-50% of the CI variance is explained by the disease burden assessed by MRI. The cognitive reserve (CR) hypothesis has been postulated to account for this discrepancy. So far, most previous studies have confirmed the CR hypothesis in MS but failed to examine CR indices collectively or use clinically relevant neuropsychological assessments. The aim of this study was to replicate previous findings for the effect of CR (and its counterpart; brain reserve-BR) in MS by considering these caveats.METHODS: 128 RRMS and 13 SPMS patients were recruited in this cross-sectional study (mean age 43.5 ± 10.4 years old, 73% females, mean disease duration 153.7 ± 89.4). CR was assessed by the Cognitive Reserve Index questionnaire (CRIq) and BR by the intracranial volume. Neuropsychological assessment was made by using the recommended for clinicians Brief International Cognitive Assessment for MS (BICAMS) tool. Other measurements included clinical characteristics, psychological status, fatigue, and MRI volumetric imaging parameters. Multiple linear regression models were implemented to ascertain the putative moderating role (i.e. interaction terms) of CR and BR in cognition.RESULTS: Exploratory univariate analyses revealed significant negative correlations between both disability and depression with cognitive scores (rho = -0.382, p < 0.001, rho = -0.278, p = 0.001, respectively), only. After controlling for gender, disability and depression, a significant moderating protective effect of CR on the associations between both grey and peripheral grey matter volumes with verbal memory was found (beta = 1.834, p = 0.045, beta = 1.936, p = 0.04 for the interaction terms, respectively). Also, BR moderated the effect of the total brain volume on verbal memory (beta = 1.516, p = 0.043).CONCLUSION: This study showed that by using composite measures of CR and simple, clinically-orientated neuropsychological assessments, the protective role of CR and BR is mostly restricted to memory function. Future research should embark on investigating interventions that will aim to enhance CR for the prevention of CI in MS.