Background: Ozanimod, an oral S1P receptor modulator, is approved in the United States and European Union for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS). A previous analysis of data from UC and multiple sclerosis (MS) open-label extension (OLE) studies showed that most patients with confirmed coronavirus infection (COVID-19) had nonserious infections, recovered, and did not require ozanimod discontinuation. As some immunomodulators and biologics may attenuate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response, this analysis evaluated humoral immune responses and predictors of response to SARS-CoV-2 vaccination in patients with RMS treated with ozanimod. Methods: RMS participants who completed a phase 1-3 ozanimod trial could enter an OLE trial (DAYBREAK; NCT02576717) of ozanimod 0.92 mg/d. This analysis (January 2020‒October 2021) included DAYBREAK participants receiving mRNA or non-mRNA SARS-CoV-2 vaccines (1 or 2 doses, vaccine-dependent) and had serum samples available postvaccination. Receptor binding domain (RBD) antibody titers were analyzed (Elecsys Anti-SARS-CoV-2 assay; Roche Diagnostics, Basel, Switzerland) prevaccination, after 1 dose, and at days 1–229 after full vaccination. Nucleocapsid antibody levels were measured before and after vaccination to confirm whether participants had a natural exposure to SARS-CoV-2, with nucleocapsid antibody negative indicating no exposure and nucleocapsid antibody positive indicating exposure to SARS-CoV-2. Fisher’s exact tests and regression models determined association with seroconversion and log2 antibody levels. Results: Demographics were similar between the mRNA and non-mRNA vaccine recipients without serological evidence of virus exposure. Seroconversion (≥0.8 U/mL spike RBD antibody) occurred in 100% (80/80) of fully vaccinated mRNA and 62% (18/29) of fully vaccinated non-mRNA vaccine recipients who were nucleocapsid antibody–negative. Additionally, seroconversion occurred in 100% (39/39) of nucleocapsid antibody–positive participants in both fully vaccinated mRNA and non-mRNA vaccine recipients. Higher spike RBD antibody levels were seen in participants with mRNA (grand mean: 512.6 U/mL, range: 1.3-4572) vs non-mRNA (grand mean: 39.3 U/mL, range: 0.4-368.5) vaccinations at all time points studied in nucleocapsid antibody–negative participants. Compared with nucleocapsid antibody–negative participants, spike RBD antibody levels were higher in fully vaccinated nucleocapsid antibody–positive participants in both mRNA and non-mRNA vaccine recipients. Vaccination with a non-mRNA vaccine predicted lower antibody levels (beta: -5.90 [95% CI: -6.99 to -4.82]; P < 0.0001) and less seroconversion (Fisher’s exact: P < 0.0001), whereas age, sex, body mass index, and absolute lymphocyte count (ALC) did not predict lower antibody levels in nucleocapsid antibody–negative participants. Conclusion(s): Participants receiving ozanimod developed humoral immune response to SARS-CoV-2 vaccines, with 100% seroconversion after mRNA vaccination; this was independent of demographic characteristics and ALC levels at time of vaccination. However, some participants developed low antibody concentrations and may benefit from booster doses. Fully vaccinated participants with confirmed evidence of natural infection had higher seroconversion rates and RBD antibody levels, possibly suggesting a primed immune response.