Acute inflammation is associated with cognitive deficits and alterations of cortical plasticity in multiple sclerosis (MS). We tested whether early treatment with high-dose interferon (IFN) beta-1a, known to reduce inflammatory activity, improves cortical function and cognitive deficits in MS. Eighty treatment-naïve relapsing-remitting MS (RRMS)patients received IFN beta-1a (44 mcg) subcutaneously three times per week. Cognitive performance and cortical plasticity were measured through the paced auditory serial addition test (PASAT) and intermittent theta burst stimulation (iTBS) before and up to two years af-ter IFN beta-1a initiation. Before treatment, patients with gadolinium-enhancing lesions (Gd+) on MRI performed worse on the PASAT,and showed lower iTBS-induced plasticity, compared with Gd- patients. Six months after treatment initiation both PASAT and iTBS-induced plasticity improved in Gd+ and remained stable in Gd- patients. These results suggest that cognitive and synaptic plasticity deficits may be rescued during high-doseIFN beta-1a treatment in newly-diagnosed RRMS patients with Gd+ lesions.