Purpose:To compare adherence and persistence among patients with multiple sclerosis (MS) initiated on disease-modifying therapy (DMTs), including intramuscular (IM) interferon beta-1a (IFNβ-1a), subcutaneous (SC) IFNβ-1a, IFNβ-1b, or glatiramer acetate (GA).Methods:MS patients initiated on IM-IFNβ-1a, SC-IFNβ-1a, IFNβ-1b, or GA between January 1, 2000 and January 2, 2008 were identified from a retrospective claims database study associated with a large US health plan. The date of DMT initiation was the index date; patients were observed for 6 months before and 12–36 months after the index date. Adherence to the index DMT was measured with a medication possession ratio (MPR), the proportion of days patients possessed their index DMTs; MPR ≥ 0.80 was considered adherent. Persistence was time in days from index date until the earlier of a minimum 60-day gap in DMT therapy or the last DMT claim during follow-up. Adherence and persistence were modeled with logistic and Cox proportional hazard regressions, respectively.Results:The study population comprised 6,680 patients in the DMT cohorts: IM-IFNβ-1a (N = 2,305, 34.5%); IFNβ-1b (N = 894, 13.4%); GA (N = 2,270, 34.0%); and SC-IFNβ-1a (N = 1,211, 18.1%). The IM-IFNβ-1a cohort had significantly higher regression-adjusted odds of adherence relative to the other cohorts: 52.4% higher odds versus the IFNβ-1b cohort (OR = 0.656, CI = 0.561–0.768); 33.5% higher odds versus the GA cohort (OR = 0.749, CI = 0.665–0.844); and 20.6% higher odds versus the SC-IFNβ-1a cohort (OR = 0.829, CI = 0.719–0.957). There were no consistent differences in persistence between the cohorts.Conclusion:IM-IFNβ-1a patients had significantly higher odds of adherence compared with other DMT cohorts, possibly attributable to IM-IFNβ-1a’s less frequent dosing schedule. The benefits of adherence may include better quality of life, lower risk of relapse, and fewer hospitalizations and emergency visits, making adherence a critical component of MS management.