Background: Switching of disease-modifying therapies (DMTs) for treatment of multiple sclerosis (MS) is driven by many factors that are not well understood. Objectives: To evaluate the clinical profile, treatment history, and drivers for DMT switching in MS patients with a focus on switching to diroximel fumarate (DRF). Methods: US healthcare providers (HCPs) completed a questionnaire and provided cross-sectional chart data from January 28 to March 1, 2021 on MS patients who switched to a new DMT within the prior 3 months. Analyses focused on switching to DRF. Results: In total, 223 HCPs (51% general neurology, 47% MS specialists, 2% other neurology) in practice for a mean of 16 years participated. Most (69%) currently prescribe DRF, 26% never prescribed DRF and 5% had previously prescribed DRF but had no patients currently taking it at the time of analysis. HCP-reported reasons for prescribing DRF included good tolerability (58%), preference for oral administration (50%), decreased number of relapses (44%) and mechanism of action (42%). Sixty-four percent thought DRF had better gastrointestinal (GI) tolerability than dimethyl fumarate (DMF). The majority thought DRF was either equivalent to or better than DMF in relation to other tolerability concerns (90%), patient satisfaction (92%), patient adherence (92%), overall safety (91%), efficacy (93%) administration/dosing (83%) and ease of treatment initiation (81%). Patient-level chart data were available for 1221 adult MS patients (mean age, 42 years); 68% were female, 70% were white and most (62%) were employed full (45%) or part (18%) time. Of these, 178 switched to DRF including 129 with relapsing-remitting MS, 22 with clinically isolated syndrome, 9 with primary-progressive MS, and 18 with secondary-progressive MS. The most common prior DMTs were DMF (30%), interferons (26%) and glatiramer acetate (25%). Reasons HCPs gave for switching audited patients from the prior DMT included efficacy (52%; primary reason, 37%), tolerability (49%; primary reason, 29%), patient request (25%; primary reason, 8%), safety (22%; primary reason, 5%) and insurance (17%; primary reason, 8%). Conclusions: Three-quarters of HCPs had experience in prescribing DRF. HCP-reported reasons for selecting DRF included good tolerability profile, oral dosing, mechanism of action and reduction in relapses. Two-thirds of HCPs perceived DRF to have a better GI tolerability profile compared to DMF. At the patient level, common reasons for switching from prior DMTs to DRF included efficacy and tolerability. Study support: Biogen.