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Disease-modifying drugs are a significant expenditure for treating multiple sclerosis. Natalizumab (NZ) has been shown to be effective in reducing relapses and disease progression. However, assessment of the cost effectiveness of NZ compared with other disease-modifying drugs in the presence of long-term data has been limited. To assess the lifetime cost effectiveness from the US healthcare and societal perspectives of glatiramer acetate (GA) and NZ (both given with symptom management) relative to symptom management alone in patients with relapsing-remitting multiple sclerosis (RRMS) using evidence from long-term published studies. A Markov model was developed with patients transitioning through health states based on Kurtzke's expanded disability status scale (EDSS). Patients were >/=18 years of age with RRMS, EDSS <6.0 and receiving treatment. Treatment effects were obtained from clinical trials for years 1 and 2 of therapy and long-term clinical assessments thereafter. Transitions were adjusted for discontinuation and persistent NZ antibodies. Patients incurred drug, other medical and lost worker productivity costs. Patient quality of life was considered in the form of utilities, which were taken from assessments of patients with MS. Costs were valued in 2007 $US, and costs and outcomes were discounted at 3% per annum. Various parameters and assumptions were tested in one-way sensitivity analyses, and scenario-based analyses were also performed. Remaining lifetime, direct medical costs for patients receiving GA or NZ versus symptom management were $US408 000, $US422 208 and $US341 436, respectively. Patients receiving GA or NZ benefited from increased years in EDSS 0.0-5.5 (1.18 and 1.09, respectively), years relapse-free (1.30 and 1.18) and QALYs (0.1341 and 0.1332). The incremental cost per QALY for GA or NZ compared with symptom management was $US496 222 and $US606 228, respectively, excluding lost worker productivity costs. GA was associated with a cost saving compared with NZ. The incremental cost per QALY results were sensitive to changes in time horizon, disease progression and drug costs. Improved QALYs for NZ were sensitive to changes in the clinical effect of NZ on disease progression and discontinuation over time. GA or NZ in RRMS patients is associated with increased benefits compared with symptom management, albeit at higher costs. Although year 1 and 2 disease progression and relapse rates were better for NZ than GA, long-term evidence may show GA to have similar, if not improved, clinical benefit