Natalizumab is the first selective adhesion molecule inhibitor indicated for treatment of active relapsing-remitting multiple sclerosis (RRMS). Natalizumab has been available in France since April 2007. The aims of this study are to analyze demographic, clinical, and tolerance data from French patients with RRMS treated with natalizumab in actual clinical practice and to draw comparisons with patients in the pivotal AFFIRM study. All patients with RRMS in the Nord-Pas de Calais and Alsace regions of France treated with natalizumab at any time since April 2007 were included. Variables analyzed included previous treatments; disability status [Expanded Disability Status Scale (EDSS) score]; annualized relapse rate (ARR) at baseline and after 12 months of treatment; and adverse events. Data from 384 patients (72% female) were evaluated. Mean baseline EDSS score was 3.53 and mean baseline ARR was 2.19, both significantly greater than in AFFIRM. One hundred twenty-seven patients completed 12 months of treatment; mean EDSS score in this group was 3.02 (14% reduction) and mean ARR was 0.59 (73% reduction). Although these patients had significantly different baseline characteristics and greater disability compared with patients receiving natalizumab in AFFIRM, average disability remained stable and ARR declined by 73%. Tolerability was similar to that observed in AFFIRM.