Background: Sphingosine-1-phosphate (S1P) receptor modulators is a new group that possesses some advantages over the other conventional therapy for multiple sclerosis. Aim of the review: The aim is to assess the efficacy and safety of sphingosine-1-phosphate receptor modulators. Methods: The protocol has been developed based on the PRISMA-P checklist by using (PICO [population, intervention, comparators, and outcome]) items, for adult subjects who have received Sphingosine-1-phosphate (S1P) receptor modulators (amiselimod; ozanimod; ponesimod; siponimod) in randomized clinical trials. The subjects with multiple sclerosis (population) receiving sphingosine-1-phosphate receptor modulator (intervention) will be compared to placebo or other modalities of multiple sclerosis (comparators), for the non-inferiority or superiority in terms of effects on walk, disability, relapse and/or other disease clinical markers (outcome). The secondary safety outcomes such as treatment-emergent adverse events and Quality of Life-54 will be assessed as well. The RevMan will be used to quantify the synthesis of data. Whereas I2 index, tau squared, and the Q-test P value will be used to examine heterogeneity among individual trials’ effect sizes. Conclusion: This protocol will report the differences in the efficacy and safety of sphingosine-1-phosphate receptor modulators (intervention) as compared to the placebo or other modalities (comparators). © 2020 EManuscript Technologies. All rights reserved.