Background: multiple sclerosis is an inflammatory demyelinating disease with a neurodegenerative component mainly characterized by progressive accumulation of focal white matter (WM) lesions. The degree of cortical damage at baseline was associated with the progression of disability. Cognitive deficits could be better explained by cortical lesions (CLs) than by WM lesions. Fatigue in MS could be due to damage to the cortico striato thalamo cortical circuit. Aim of the Work: to detect (CLs) in MS patients and correlate these lesions with physical disability, cognitive dysfunction and fatigue. Subjects and Methods: a case-control study on 64 subjects including 44 known multiple sclerosis patients diagnosed according to revised McDonald's criteria 2017. Results: we observed a statistically significant difference between MS patients and healthy controls as regard number of (CLs), Symbol Digit Modality Test (SDMT), Fatigue Severity Scale (FSS) and P300 wave latencies and amplitudes. Secondary progressive (SPMS) subgroup was affected more than relapsing remitting (RRMS) subgroup. (CLs) were located mainly in temporal lobes. Conclusion: This study suggested that cortical affection is directly associated with physical and cognitive disability progression.