OBJECTIVES:  To evaluate healthcare resource use (HCRU) among newly diagnosed patients with multiple sclerosis (MS) initiating self-injectable versus oral disease-modifying drugs (DMDs) in a large, nationwide US electronic health record (EHR) database. METHODS:  Newly diagnosed patients with MS (International Classification of Diseases, Ninth Revision, Clinical Modification code: 340.xx) initiating a self-injectable or oral DMD (first DMD=index date) were identified from the Optum-Humedica database between 1/1/2008 and 12/31/2014. Patients were required to have 1-year continuous eligibility pre- and post-index and no prior DMD use. Baseline and follow-up HCRU, including outpatient encounters, inpatient admissions, emergency department (ED) visits, magnetic resonance imaging (MRI), and blood tests, were stratified by self-injectable and oral DMD cohorts. RESULTS:  Among the 7599 patients with newly diagnosed MS who met the inclusion criteria, 6958 (92%) initiated treatment with a self-injectable DMD and 641 (8%) initiated treatment with an oral DMD. Comparing pre- and post-index, the proportion of oral initiators with an inpatient admission increased 19.0% (from 7.9% to 9.4%) and the proportion with ED visits increased 30.8% (from 14.3% to 18.7%). Self-injectable initiators had a 7.0% decrease in inpatient admissions (from 10.0% to 9.3%) and an 11.2% increase in ED visits (11.6% to 12.9%). The proportion with outpatient visits was high in both groups pre- and post-index (orals: 99.7% pre-index and 99.8% post-index; self-injectables: 99.4% pre-index and 99.9% post-index). The proportion with MRIs decreased 10.1% for oral initiators (from 39.6% to 35.6%) and increased 5.4% for self-injectable initiators (from 31.4% to 33.1%), and the proportion with blood tests increased for both cohorts (orals: from 73.3% to 80.0% [9.1% increase]; self-injectables: from 62.1% to 72.3% [16.4% increase]). CONCLUSIONS:  This EHR study showed that HCRU differs between newly diagnosed patients with MS initiating self-injectable DMDs compared with those initiating an oral DMDs. Further research is needed to better understand the reasons for these differences.