Objective: Natalizumab is a new disease modifying therapy currently licensed for use in patients with relapsing-remitting multiple sclerosis (RRMS), and has recently been the subject of a cost-effectiveness evaluation by the National Institute for Health and Clinical Excellence (NICE) in the UK. NICE accepted that natalizumab was cost-effective in a highly-active subgroup of RRMS patients, but not in all patients failing on current therapy (sub-optimal therapy, SOT patients). In the SOT patients, the basecase ICERs exceeded £43,400 and NICE essentially concluded that natalizumab would not be a cost-effective use of NHS resources in these patients unless they were having two or more relapses per year. However, NICE recognised that the evaluation may have underestimated the incremental QALY in two areas. The first was that the relapse disutility was underestimated, and the second was that the time horizon of the evaluation was too short. Here we re-evaluated the ICERs for natalizumab vs. interferon-beta and glatiramer acetate in SOT patients taking into account the points raised by NICE. Methods: The original model submitted to NICE was a 20-year markov-model parameterised for the UK from a direct health-care perspective. Disutilities for relapse were updated using values from a previous UK Health Technology Assessment, and the cost of relapse was changed in line with contemporary studies. The time-horizon for the model was extended from 20 years to 30 years. Results: The ICER from a direct medical costs perspective for natalizumab vs. interferon-beta was £29,900 per QALY. For natalizumab vs. glatiramer acetate the ICER was £29,300 per QALY. Conclusion: The European Medicines Evaluation Agency has approved natalizumab for use in highly active RRMS, including SOT patients. Given the willingness-to-pay threshold of £30,000 per QALY commonly associated with NICE guidance, the results here show that natalizumab is a cost-effective treatment for all patients failing on current therapy in the UK.