Background: Sphingosine-1-phosphate receptor modulators (S1Ps), a class of oral disease-modifying therapies (DMTs) for multiple sclerosis (MS), are cell-trafficking inhibitors that have been shown to have high efficacy. Each S1P has different recommendations for clinical management events, as described in their United States Prescribing Information (USPI), which may impact the overall ease of use. Objectives: To estimate the expected number of differential clinical management events before and during treatment with S1Ps. Methods: Clinically relevant differences in management events were identified from the USPI of each S1P. Excluding common class labelling recommendations, clinical management events prior to initiation were first-dose monitoring, genotyping, and an eye exam; after initiation events were drug-drug interactions (DDIs), eye exam, and liver function test. As appropriate, recommendations in USPIs were applied directly to quantify event frequency. Other events were quantified based on real-world data from 3 US administrative claims databases. Adult MS-treated patients were identified from 1/2016-3/2019 with 1-year continuous enrolment pre- and post-index (first DMT claim date meeting inclusion criteria). The outcomes of interest were the proportion of patients for which first-dose monitoring and an eye exam is recommended, and the average number of DDI drugs used concomitantly with any MS DMTs within a 1-year period (excluding DDI drugs common to all S1Ps). Results: In the IBM MarketScan Commercial Claims database, first-dose monitoring is recommended in all patients before fingolimod initiation compared with 9% for siponimod or ponesimod and 0% for ozanimod. An eye exam is recommended in all patients before fingolimod, siponimod, and ponesimod initiation compared with 9% for ozanimod. For siponimod, genotyping is recommended for all patients. Periodic liver function tests and an eye exam is recommended for all patients 3-4 months after initiating fingolimod. Average numbers of DDI drugs used concomitantly with any MS DMTs within 1 year were 0.0005, 0.0976, 1.7616, and 0.0185 for fingolimod, siponimod, ozanimod, and ponesimod, respectively. Overall, a fingolimod patient is expected to have 4.0 unique clinical management events compared with 2.2 for siponimod, 1.9 for ozanimod, and 1.1 for ponesimod. Similar results were observed in 2 other claims databases. Conclusions: Ponesimod is expected to have the fewest clinical management events among S1Ps.