Background: Little is known about the factors associated with the selection of Disease Modifying Agents (DMA) for the management of Multiple Sclerosis (MS) since the introduction of oral DMAs in 2010., Objectives: To examine the factors associated with initiation of oral DMAs in patients with MS using data from electronic medical records (EMR)., Methods: A retrospective longitudinal study was conducted using TriNetX, a federated EMR network of over 38 million patients from the US, from 2009-2019. Adult (≥18 years) patients with MS from the United States were identified using a MS diagnosis (ICD-9-CM: 340 or ICD-10-CM: G35) and a newly prescribed DMA with a one-year baseline period. Patients with new DMA prescriptions were classified as oral or injectable users based on their index medication. A multivariable logistic regression model was used to determine the predisposing (age category, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, symptomatic medication, and healthcare utilization) associated with initiation of an oral versus injectable DMA., Results: The study cohort consisted of 7,511 MS patients with a newly prescribed DMA, of whom most were 18-44 years old (48.33%), female (75.18%), and white (80.92%). About 42.32% of MS patients were diagnosed with at least one comorbidity (mean±SD: 0.86±1.37). Two thirds (66.32%) of the patients with MS started injectable DMAs, and the remaining one third (33.68%) started oral DMAs. Multivariable regression revealed that middle-aged (45-64 years; Adjusted Odds Ratio [aOR]=0.88; 95% Confidence Interval [CI]: 0.79-0.98) and older adults (≥65 years; aOR=0.67, 95% CI: 0.53-0.84) were associated with a decreased likelihood of receiving oral DMAs. The presence of general symptoms (aOR=1.26, 95% CI: 1.10-1.45) and cerebellar symptoms (aOR=1.56, 95% CI: 1.26-1.93) was associated with an increased likelihood of an oral DMA. However, the presence of sensory symptoms (aOR: 0.72, 95% CI: 0.59-0.88) was associated with a decreased likelihood of an oral DMA. Comorbidities such as renal failure (aOR=0.16, 95%% 0.04-0.62), obesity (aOR=0.60, 95% CI: 0.45-0.80), drug abuse (aOR=0.61, 95% CI: 0.38-0.99), and other neurological disorders (aOR=0.82, 95% CI: 0.69-0.96) were associated with a decreased likelihood of receiving an oral DMA prescription. While the use of analgesics (aOR=0.78, 95% CI: 0.69-0.88) was associated with decreased likelihood, the use of antispasmodics (aOR=1.14, 95% CI: 1.01-1.28) was associated with an increased likelihood of receiving an oral DMA. Relative to the time-period when first oral DMAs entered into the market (2010-11), with time, the likelihood of prescribing oral DMA increased by multiple folds (2012-13, aOR=4.30, 95% CI: 3.08-6.00; 2014-15, aOR=19.34, 95% CI: 14.10-26.54; 2016-17, aOR=17.63, 95% CI: 12.76-24.35; and 2018-19, aOR=20.73, 95% CI: 14.64-29.37)., Conclusions: Oral DMA use steadily increased over the years, with one in three MS patients receiving oral agents. Both demographic and clinical factors were associated with the initiation of oral DMA over injectable DMA., Competing Interests: Declaration of Competing Interest George J Hutton reports grants from Biogen, Novartis, MedImmune, Hoffman-LaRoche, EMD Serono, Sanofi,and Mallinckrodt, and personal fees from Novartis, Sanofi, Celgene, outside the submitted work. Rajender R Aparasu reports grants from Incyte, Novartis, and Astellas outside the submitted work. We wish to confirm that there are no other known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome., (Copyright © 2020 Elsevier B.V. All rights reserved.)