OBJECTIVES: To assess real-world effectiveness, based on registry data, of natalizumab in multiple sclerosis (MS) patients with highly active relapsing-remitting MS (RRMS). METHODS: Phase IV, observational, retrospective, multi-center database analysis on data from the period January 2009 – January 2013.  Statistical analyses were performed using Kaplan-Meier and Cox PH regression. Inclusion criteria comprised adults aged ≥18 with high disease activity with rapidly evolving severe RRMS or a relapse despite treatment with beta-interferon or glatiramer acetate. The main outcome measure was change from annualized baseline relapse rate (ARR), with secondary endpoints comprising sustained disability progression and improvement at 12/24 months, and change in the mean Expanded Disability Status Scale (EDSS).  Change from baseline ARR comprised ARR absolute values, relative reduction (percentage), and percentage of patients remaining relapse-free. Analyses were presented using frequency tables, crosstabs, graphics and, for EDSS, survival analysis was conducted.  Subgroup analyses were conducted for age, gender, and prior treatment received.   RESULTS: A total of 216 individuals (72% of whom females) were included in the study.  Mean age at onset of MS was 27 years, 29 years at diagnosis, 38 years at start of natalizumab therapy.  A significant decrease in mean ARR was seen after 12 months compared to baseline (N=216; Δ=0.76; p-value<0.001), and between the first and second years of treatment (N=208; Δ=0.06; p-value=0.030).  There was no significant variation across subgroups.  Mean EDSS score decreased from 3.26 to 3.02 after 12 months of treatment. A subsequent, more in-depth analysis will be required to interpret long-term EDSS performance in detail. CONCLUSIONS: Natalizumab treatment in Hungary was associated with two-year effectiveness as shown by reduced ARR and stabilized EDSS over the observation period. These results are important for decision-makers striving to optimize spending on MS treatments and for clinical experts looking for improved understanding of the therapeutic benefit of natalizumab.