OBJECTIVES To compare cost of care for interferon beta (IFNb)-1a subcutaneous (SC) and natalizumab in patients with multiple sclerosis (MS). METHODS In this post hoc analysis, eligible patients (>18 and <65 years) had an MS diagnosis in a national managed care database, ≥1 new medical or prescription claim for IFNb-1a SC or natalizumab during the July 1, 2006 to December 31, 2006 selection period, and were continuously eligible for 12 months before and after the initial disease-modifying drug (DMD) claim in the selection period. Managed care costs represented both total and component costs. A propensity score was calculated as the probability of being in either treatment group from preperiod variables (eg, age, sex, region). Analysis of covariance was used to evaluate total and component costs by treatment cohort. RESULTS A total of 421 patients (IFNb-1a SC = 222, natalizumab = 199) met study criteria. Most patients were women (IFNb-1a SC, 77.9%; natalizumab, 74.4%), but were older in the natalizumab group (mean [SD] 45.5 [9.7] y vs 42.2 [10.7] y). DMD use differed by region, and more natalizumab patients were enrolled in HMOs (43.2% vs 32.4%). The percentage of patients with no evidence of DMD use in the preperiod was 26.6% for natalizumab and 63.5% for IFNb-1a SC. Least square (LS) means differences between IFNb-1a SC and natalizumab for total and prescription costs were a function of the number of days of exposure. At the average exposure of 290 days, total LS mean cost for IFNb-1a SC and natalizumab were $26,433 and $35,980, respectively (P<0.0001). Prescription costs were significantly higher for natalizumab compared with IFNb-1a SC ($26,775 vs $20,187; P<0.0001). Outpatient costs were significantly greater for natalizumab patients ($8640) than for IFNb-1a SC patients ($4930; P<0.0001). CONCLUSIONS Patients initiated on natalizumab had greater total, prescription, and outpatient costs than did patients initiated on IFNb-1a SC.