Ozanimod and fingolimod are sphingosine 1-phosphate receptor–modulating therapies for relapsing multiple sclerosis. Comparative effectiveness was assessed by matching adjusted indirect comparisons of safety and efficacy trial outcomes at first-dose cardiac monitoring, 1 year and 2 years. After adjustment, baseline characteristics were similar. Ozanimod was associated with a lower risk of extended first-dose monitoring, conduction abnormalities including atrioventricular block. One-year risks of any adverse event (AE), mean lymphocyte count reductions and abnormal liver enzymes were lower with ozanimod. Two-year risks of AEs leading to discontinuation, any AEs, herpetic infections, bradycardia and abnormal liver enzymes were lower with ozanimod. Analyses of efficacy outcomes were similar. Ozanimod appears to have a favorable benefit-risk profile versus fingolimod.