Natalizumab has been demonstrated to be highly effective in reducing measures of disease activity, such as clinical relapse rate, and gadolinium (Gd)-enhancing and new or enlarging T2 lesions appearance in patients with relapsing remitting multiple sclerosis (RRMS). Up to date, no data on the effect of natalizumab on cortical pathology have been published. We studied the efficacy of natalizumab in preventing the accumulation of new cortical lesions (CL) in 35 RRMS patients treated for 1 year. While confirming the high impact of natalizumab in reducing the relapse rate (>90%, 85% relapse-free patients) and white matter (WM) pathology (80% patients free from new T2 WM lesions, 97% patients free from new T1 Gd-enhancing lesions), we found that this monoclonal antibody was highly effective in reducing the appearance of new CL (86% patients free from new CL). Our findings indicate a relevant activity of natalizumab against cortical inflammation in RRMS.