Background: The COVID-19 epidemic raises important questions about the efficacy of vaccines for people treated with ocrelizumab (OCR), an anti-CD20 therapy. OCR has been shown to reduce the humoral response to SARS-CoV-2 infection and vaccination, but the T-cell response to vaccination has not been fully characterized. Objectives: We sought to provide data regarding B and T-cell mediated responses to SARS-CoV-2 vaccination in OCR-treated patients, and to determine which variables correlate with vaccine immunogenicity. Methods: We conducted a prospective, observational, single center cohort study of patients with MS treated with either OCR or natalizumab (TYS) as a comparator between March 2, 2021, and July 1, 2021. Eligible patients were age 18 to 55 and had no known prior infection with, or vaccination against, SARS-CoV-2. Patients with prior use of immunosuppressive or chemotherapeutic agents, or treatment with any anti-CD20 therapy other than OCR within 12 months of enrollment, were excluded. The Roche Elecsys anti-SARS-CoV-2 S immunoassay was performed prior to and 3-4 weeks post vaccination to evaluate the antibody response to SARS-CoV-2 spike IgG. The Adaptive Biotechnologies T-Detect COVID Test was performed to evaluate the adaptive T-cell immune response to SARS-CoV-2 in OCR-treated patients with no detectable antibodies. Results: Forty-eight patients were enrolled in the study, 69% treated with OCR and 31% treated with TYS. Eighteen percent of OCR and 100% of TYS patients had a positive antibody response. In OCR-treated patients, there was no correlation between age, sex, BMI, total number of infusions, IgG, CD19, or ALC and antibody response. There was a trend suggesting that a longer interval between the last infusion and vaccination increased the likelihood of producing antibodies (P=0.062). All OCR patients with negative antibody responses had positive adaptive T-cell responses. Conclusions: Treatment with OCR impaired the humoral response to SAR-CoV-2 vaccination, with only 18% of patients having a detectable antibody response. However, all patients without measurable antibodies had SARS-CoV-2 specific T-cell responses. Further research is needed to determine if the T-cell response to SARS-CoV-2 vaccination is sufficient to prevent infection or reduce severity of COVID in patients who did not produce antibodies.