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Objectives Gray matter (GM) damage is well known as a fundamental aspect of multiple sclerosis (MS). Above all, cortical lesions (CLs) burden, detectable at MRI with double inversion recovery (DIR) sequences, has been demonstrated to correlate with cognitive impairment (CI). The aim of this study was to investigate the role of CLs number in predicting CI in a cohort of patients with MS in a clinical practice setting. Materials and methods Thirty consecutive patients with MS presenting CLs (CL+) at high-field (3.0 T) MRI 3D-DIR sequences and an even group of MS patients without CLs (CL-) as a control, were investigated with the Rao Brief Repeatable Battery of Neuropsychological Tests (BRB), Version A. Total and lobar CLs number were computed in CL+ patients. Results Among the sixty patients with MS enrolled, forty-seven (78.3%) had a relapsing-remitting course, while thirteen (21.7%) a progressive one, eleven secondary progressive, and two primary progressive. Compared to CL-, CL+ patients had a greater proportion of progressive forms (p = .03). The most affected region was the frontal lobe (73.3% of patients), followed by temporal and parietal ones (both 60.0%). Multivariate (logistic regression) analysis revealed a significant correlation between total CLs number and the presence of mild cognitive impairment defined as pathologic score in at least one BRB test (p = .04); it was also correlated with deficit at PASAT 3 (p = .05) and Stroop Test (p = .02). Conclusions We confirmed CLs number, evaluated with a technique quite commonly available in clinical practice, as a predictive factor of CI in patients with MS, in order to improve the diagnosis and management of CI and monitor potential neuroprotective effects of therapies.